Inhibitors of tyrosine kinases

ABSTRACT

The invention relates to compounds of formula  
                 
wherein the substituents R1, R2 and R4 have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, especially a neoplastic disease, in particular leukaemia, and a method for the treatment of such a disease.

The invention relates to novel substituted pyrimidinylaminobenzamides,processes for the preparation thereof, pharmaceutical compositionscontaining same, the use thereof optionally in combination with one ormore other pharmaceutically active compounds for the therapy of adisease which responds to an inhibition of protein kinase activity,especially a neoplastic disease, in particular leukaemia, and a methodfor the treatment of such a disease.

BACKGROUND OF THE INVENTION

Protein kinases (PKs) are enzymes which catalyze the phosphorylation ofspecific serine, threonine or tyrosine residues in cellular proteins.These post-translational modifications of substrate proteins act asmolecular switches regulating cell proliferation, activation and/ordifferentiation. Aberrant or excessive PK activity has been observed inmany disease states including benign and malignant proliferativedisorders. In a number of cases, it has been possible to treat diseases,such as proliferative disorders, by making use of PK inhibitors in vitroand in vivo.

In view of the large number of protein kinase inhibitors and themultitude of proliferative and other PK-related diseases, there is anever-existing need to provide novel classes of compounds that are usefulas PK inhibitors and thus in the treatment of these PTK relateddiseases. What is required are new classes of pharmaceuticallyadvantageous PK inhibiting compounds.

The Philadelphia Chromosome is a hallmark for chronic myelogenousleukaemia (CML) and carries a hybrid gene that contains N-terminal exonsof the bcr gene and the major C-terminal part (exons 2-11) of the c-ablgene. The gene product is a 210 kD protein (p210 Bcr-Abl). The Abl-partof the Bcr-Abl protein contains the abl-tyrosine kinase which is tightlyregulated in the wild type c-abl, but constitutively activated in theBcr-Abl fusion protein. This deregulated tyrosine kinase interacts withmultiple cellular signalling pathways leading to transformation andderegulated proliferation of the cells (Lugo et al., Science 247, 1079[1990]).

General Description of the Invention

It has now been found that various compounds of thepyrimidinylaminobenzamide class show inhibition of protein kinaseactivity. The compounds of formula I, described below in more detail,especially show inhibition of one or more tyrosine kinases, such asc-Abl, Bcr-Abl, the receptor tyrosine kinases PDGF-R, Flt3, VEGF-R,EGF-R, and c-Kit, as well as combinations of two or more of these; inthe case of novel pyrimidinylaminobenzamides according to the invention,the compounds are appropriate for the inhibition of these and/or otherprotein kinases, especially those mentioned above and/or for theinhibition of mutants of these enzymes, especially of Bcr-Abl, forexample the Glu255->Valine mutant. In view of these activities, thecompounds can be used for the treatment of diseases related toespecially aberrant or excessive activity of such types of kinases,especially those mentioned.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a compound of formula I,

whereinR₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, or phenyl-lower alkyl;R₂ represents hydrogen, lower alkyl, optionally substituted by one ormore identical or different radicals R₃, cycloalkyl, benzcycloalkyl,heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl groupcomprising zero, one, two or three ring nitrogen atoms and zero or oneoxygen atom and zero or one sulfur atom, which groups in each case areunsubstituted or mono- or polysubstituted;and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an arylgroup, or a mono- or bicyclic heteroaryl group comprising zero, one, twoor three ring nitrogen atoms and zero or one oxygen atom and zero or onesulfur atom, which groups in each case are unsubstituted or mono- orpolysubstituted;or wherein R₁ and R₂ together represent alkylene with four, five or sixcarbon atoms optionally mono- or disubstituted by lower alkyl,cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- ordisubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl;benzalkylene with four or five carbon atoms; oxaalkylene with one oxygenand three or four carbon atoms; or azaalkylene with one nitrogen andthree or four carbon atoms wherein nitrogen is unsubstituted orsubstituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl,N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, loweralkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl,pyrimidinyl, or pyrazinyl;R₄ represents hydrogen, lower alkyl, or halogen;and a N-oxide or a pharmaceutically acceptable salt of such a compound.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either linear or branched withsingle or multiple branching.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration. Thecompounds may thus be present as mixtures of isomers or as pure isomers,preferably as enantiomer-pure diastereomers.

The invention relates also to possible tautomers of the compounds offormula I.

Lower alkyl is preferably alkyl with from and including 1 up to andincluding 7, preferably from and including 1 to and including 4, and islinear or branched; preferably, lower alkyl is butyl, such as n-butyl,sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl,ethyl or methyl. Preferably lower alkyl is methyl, propyl or tert-butyl.

Lower acyl is preferably formyl or lower alkylcarbonyl, in particularacetyl.

An aryl group is an aromatic radical which is bound to the molecule viaa bond located at an aromatic ring carbon atom of the radical. In apreferred embodiment, aryl is an aromatic radical having 6 to 14 carbonatoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl orphenanthrenyl, and is unsubstituted or substituted by one or more,preferably up to three, especially one or two substituents, especiallyselected from amino, mono- or disubstituted amino, halogen, lower alkyl,substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy,etherified or esterified hydroxy, nitro, cyano, carboxy, esterifiedcarboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N,N-disubstitutedcarbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio,phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, loweralkylsulfinyl, phenylsulfinyl, phenyl-lower alkylsulfinyl, loweralkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-loweralkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkylmercapto,halogen-lower alkylsulfonyl, such as especiallytrifluoromethanesulfonyl, dihydroxybora (—B(OH)₂), heterocyclyl, a mono-or bicyclic heteroaryl group and lower alkylene dioxy bound at adjacentC-atoms of the ring, such as methylene dioxy. Aryl is more preferablyphenyl, naphthyl or tetrahydronaphthyl, which in each case is eitherunsubstituted or independently substituted by one or two substituentsselected from the group comprising halogen, especially fluorine,chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyl, e.g.by methyl, by halogen-lower alkyl, e.g. trifluoromethyl, or by phenyl;lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy,lower alkyl, e.g. methyl or propyl; halogen-lower alkyl, e.g.trifluoromethyl; hydroxy-lower alkyl, e.g. hydroxymethyl or2-hydroxy-2-propyl; lower alkoxy-lower alkyl; e.g. methoxymethyl or2-methoxyethyl; lower alkoxycarbonyl-lower alkyl, e.g.methoxy-carbonylmethyl; lower alkynyl, such as 1-propynyl; esterifiedcarboxy, especially lower alkoxycarbonyl, e.g. methoxycarbonyl,n-propoxy carbonyl or iso-propoxy carbonyl; N-mono-substitutedcarbamoyl, in particular carbamoyl monosubstituted by lower alkyl, e.g.methyl, n-propyl or iso-propyl; amino; lower alkylamino, e.g.methylamino; di-lower alkylamino, e.g. dimethylamino or diethylamino;lower alkylene-amino, e.g. pyrrolidino or piperidino; loweroxaalkylene-amino, e.g. morpholino, lower azaalkylene-amino, e.g.piperazino, acylamino, e.g. acetylamino or benzoylamino; loweralkylsulfonyl, e.g. methylsulfonyl; sulfamoyl; or phenylsulfonyl.

A cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl orcycloheptyl, and may be unsubstituted or substituted by one or more,especially one or two, substitutents selected from the group definedabove as substitutents for aryl, most preferably by lower alkyl, such asmethyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and furtherby oxo or fused to a benzo ring, such as in benzcyclopentyl orbenzcyclohexyl.

Substituted alkyl is alkyl as last defined, especially lower alkyl,preferably methyl; where one or more, especially up to three,substituents may be present, primarily from the group selected fromhalogen, especially fluorine, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, loweralkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl isespecially preferred.

Mono- or disubstituted amino is especially amino substituted by one ortwo radicals selected independently of one another from lower alkyl,such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; loweralkoxy lower alkyl, such as methoxy ethyl; phenyl-lower alkyl, such asbenzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl;substituted benzoyl, wherein the phenyl radical is especiallysubstituted by one or more, preferably one or two, substituents selectedfrom nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino,hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, andcarbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radicalis unsubstituted or especially substituted by one or more, preferablyone or two, substituents selected from nitro, amino, halogen, N-loweralkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, loweralkoxycarbonyl, lower alkanoyl, and carbamoyl; and is preferably N-loweralkylamino, such as N-methylamino, hydroxy-lower alkylamino, such as2-hydroxyethylamino or 2-hydroxypropyl, lower alkoxy lower alkyl, suchas methoxy ethyl, phenyl-lower alkylamino, such as benzylamino,N,N-di-lower alkylamino, N-phenyl-lower alkyl-N-lower alkylamino,N,N-di-lower alkylphenylamino, lower alkanoylamino, such as acetylamino,or a substituent selected from the group comprising benzoylamino andphenyl-lower alkoxycarbonylamino, wherein the phenyl radical in eachcase is unsubstituted or especially substituted by nitro or amino, oralso by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino,hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoylor aminocarbonylamino. Disubstituted amino is also lower alkylene-amino,e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; loweroxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g.piperazino or N-substituted piperazino, such as N-methylpiperazino orN-methoxycarbonylpiperazino.

Halogen is especially fluorine, chlorine, bromine, or iodine, especiallyfluorine, chlorine, or bromine.

Etherified hydroxy is especially C₈-C₂₀alkyloxy, such as n-decyloxy,lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, ortert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy,halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono-or bicyclic hetero-aryl comprising one or two nitrogen atoms, preferablylower alkoxy which is substituted by imidazolyl, such as1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl,pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl,quinolinyl, indolyl or thiazolyl.

Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, loweralkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-loweralkoxycarbonyloxy, such as benzyloxycarbonyloxy.

Esterified carboxy is especially lower alkoxycarbonyl, such astert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl orethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.

Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g.acetyl.

N-Mono- or N,N-disubstituted carbamoyl is especially substituted by oneor two substituents independently selected from lower alkyl,phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-loweralkylene or aza-lower alkylene optionally substituted at the terminalnitrogen atom.

A mono- or bicyclic heteroaryl group comprising zero, one, two or threering nitrogen atoms and zero or one oxygen atom and zero or one sulfuratom, which groups in each case are unsubstituted or mono- orpolysubstituted, refers to a heterocyclic moiety that is unsaturated inthe ring binding the heteroaryl radical to the rest of the molecule informula I and is preferably a ring, where in the binding ring, butoptionally also in any annealed ring, at least one carbon atom isreplaced by a heteroatom selected from the group consisting of nitrogen,oxygen and sulfur; where the binding ring preferably has 5 to 12, morepreferably 5 or 6 ring atoms; and which may be unsubstituted orsubstituted by one or more, especially one or two, substitutentsselected from the group defined above as substitutents for aryl, mostpreferably by lower alkyl, such as methyl, lower alkoxy, such as methoxyor ethoxy, or hydroxy. Preferably the mono- or bicyclic heteroaryl groupis selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl,pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalyl, quinazolinyl, quinnolinyl, pteridinyl,indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl,benzo[d]pyrazolyl, thienyl and furanyl. More preferably the mono- orbicyclic heteroaryl group is selected from the group consisting ofpyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl,isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl,benzo[d]pyrazolyl, thienyl, and furanyl. In one preferred embodiment ofthe invention the pyridyl radical is substituted by hydroxy in orthoposition to the nitrogen atom and hence exists at least partially in theform of the corresponding tautomer which is pyridin-(1H)2-one. Inanother preferred embodiment, the pyrimidinyl radical is substituted byhydroxy both in position 2 and 4 and hence exists in several tautomericforms, e.g. as pyrimidine-(1H, 3H)2,4-dione.

Heterocyclyl is especially a five, six or seven-membered heterocyclicsystem with one or two heteroatoms selected from the group comprisingnitrogen, oxygen, and sulfur, which may be unsaturated or wholly orpartly saturated, and is unsubstituted or substituted especially bylower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, orheteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl,N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-loweralkyl-piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl,2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl, or2-methyl-1,3-dioxolan-2-yl.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula I. Such salts are formed, for example, as acid additionsalts, preferably with organic or inorganic acids, from compounds offormula I with a basic nitrogen atom, especially the pharmaceuticallyacceptable salts. Suitable inorganic acids are, for example, halogenacids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.Suitable organic acids are, for example, carboxylic, phosphonic,sulfonic or sulfamic acids, for example acetic acid, propionic acid,octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lacticacid, fumaric acid, succinic acid, adipic acid, pimelic acid, subericacid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids,such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylicacid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalicacid, phenylacetic acid, mandelic acid, cinnamic acid, methane- orethane-sulfonic acid, 2-hydroxyethanesulfonic acid,ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonicacid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonicacid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, or ammonium salts withammonia or suitable organic amines, such as tertiary monoamines, forexample triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.

When a basic group and an acid group are present in the same molecule, acompound of formula I may also form internal salts.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

In view of the close relationship between the novel compounds in freeform and those in the form of their salts, including those salts thatcan be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the freecompounds hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient.

The compounds of formula I and N-oxides thereof have valuablepharmacological properties, as described hereinbefore and hereinafter.

The efficacy of the compounds of the invention as inhibitors of c-Abl,Bcr-Abl, and VEGF-receptor tyrosine kinase activity can be demonstratedas follows:

Test for activity against c-Abl protein tyrosine kinase. The test isconducted as a filter binding assay as follows: The His-tagged kinasedomain of c-Abl is cloned and expressed in the baculovirus/Sf9 system asdescribed by Bhat et al., J Biol. Chem. 272, 16170-5 (1997). A proteinof 37 kD (c-Abl kinase) is purified by a two-step procedure over aCobalt metal chelate column followed by an anion exchange column with ayield of 1-2 mg/L of Sf9 cells. The purity of the c-Abl kinase is >90%as judged by SDS-PAGE after Coomassie blue staining. The assay contains:c-Abl kinase (50 ng), 20 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 10 μM Na₃VO₄,1 mM DTT and 0.06 μCi/assay [(γ³³ P]-ATP (5 μM ATP) using 30 μg/mLpoly-Ala,Glu,Lys,Tyr-6:2:5:1 (Poly-AEKY, Sigma P1152) in the presence of1% DMSO, total volume of 30 μL. Reactions are terminated by adding 10 μLof 250 mM EDTA, and 30 μL of the reaction mixture is transferred ontoImmobilon-PVDF membrane (Millipore, Bedford, Mass., USA) previouslysoaked for 5 min with methanol, rinsed with water, then soaked for 5 minwith 0.5% H₃PO₄ and mounted on vacuum manifold with disconnected vacuumsource. After spotting all samples, vacuum is connected and each wellrinsed with 200 μL 0.5% H₃PO₄. Membranes are removed and washed on ashaker with 0.5% H₃PO₄ (4 times) and once with ethanol. Membranes arecounted after drying at ambient temperature, mounting in PackardTopCount 96-well frame, and addition of 10 μL/well of Microscint™(Packard).

Test for activity against Bcr-Abl. The murine myeloid progenitor cellline 32Dcl3 transfected with the p210 Bcr-Abl expression vectorpGDp210Bcr/Abl (32D-ber/abl) was obtained from J. Griffin (Dana FaberCancer Institue, Bosten, Mass., USA). The cells express the fusionBcr-Abl protein with a constitutively active abl kinase and proliferategrowth factor independent. The cells are expanded in RPMI 1640 (AMIMED),10% fetal calf serum, 2 mM glutamine (Gibco) (“complete medium”), and aworking stock is prepared by freezing aliquots of 2×10⁶ cells per vialin freezing medium (95% FCS, 5% DMSO (SIGMA)). After thawing, the cellsare used during maximally 10-12 passages for the experiments.

For cellular assays, compounds are dissolved in DMSO and diluted withcomplete medium to yield a starting concentration of 10 μM followed bypreparation of serial 3-fold dilutions in complete medium. 200'00032D-Bcr/Abl cells in 50 μL complete medium are seeded per well in 96well round bottom tissue culture plates. 50 μL per well of serial 3-folddilutions of the test compound are added to the cells in triplicates.Untreated cells are used as control. The compound is incubated togetherwith the cells for 90 min at 37° C., 5% CO₂, followed by centrifugationof the tissue culture plates at 1300 rpm (Beckmann GPR centrifuge) andremoval of the supernatants by careful aspiration taking care not toremove any of the pelleted cells. The cell pellets are lysed by additionof 150 μL lysis buffer (50 mM Tris/HCl, pH 7.4,150 mM sodium chloride, 5mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodium ortho-vanadate, 1 mM PMSF, 50μg/mL aprotinin and 80 μg/mL leupeptin) and either used immediatedly forthe ELISA or stored frozen in the plates at −20° C. until usage. BlackELISA plates (Packard HTRF-96 black plates) are precoated over night at4° C. with 50 ng/well of the rabbit polyclonal anti-abl-SH3 domain Ab06-466 from Upstate in 50 μL PBS. After washing 3 times with 200 μL/wellPBS containing 0.05% Tween20 (PBST) and 0.5% TopBlock (Juro), residualprotein binding sites are blocked with 200 μL/well PBST, 3% TopBlock for4 h at room temperature followed by incubation with 50 μL lysates ofuntreated or compound-treated cells (20 μg total protein per well) for3-4 h at 4° C. After 3 washings, 50 μL/well anti-phosphotyrosine AbPY20(AP) labeled with alkaline phosphatase (Zymed) diluted to 0.2 μg/mLin blocking buffer is added and incubated over night (4° C.). For allincubation steps the plates are covered with plate sealers (Costar).Finally, the plates are washed another three times with washing bufferand once with deionized water before addition of 90 μL/well of theAP-substrate CDPStar RTU with Emerald II. The plates, now sealed withPackard TopSeal™-A plate sealers, are incubated for 45 min at roomtemperature in the dark and luminescence is quantified by measuringcounts per second (CPS) with a Packard Top Count MicroplateScintillation Counter (Top Count). The difference between theELISA-readout (CPS) obtained for with the lysates of the untreated32D-Bcr/Abl cells and the readout for the assay-background (allcomponents, but without cell lysate) is calculated and taken as 100%reflecting the constitutively phosphorylated Bcr-Abl protein present inthese cells. The activity of the compound on the Bcr-Abl kinase activityis expressed as percent reduction of the Bcr-Abl phosphorylation. Thevalues for the IC₅₀ and IC₉₀ are determined from the dose responsecurves by graphical extrapolation.

Test for activity against VEGF-receptor tyrosine kinase. The test isconducted using Flt-1 VEGF-receptor tyrosine kinase. The detailedprocedure is as follows: 30 μL kinase solution (10 ng of the kinasedomain of Flt-1, Shibuya et al., Oncogene 5, 519-24 [1990]) in 20 mMTris.HCl pH 7.5, 3 mM manganese dichloride (MnCl₂), 3 mM magnesiumchloride (MgCl₂), 10 μM sodium vanadate, 0.25 mg/mL polyethylenglycol(PEG) 20000, 1 mM dithiothreitol and 3 μg/μL poly(Glu,Tyr) 4:1 (Sigma,Buchs, Switzerland), 8 μM [³³P]-ATP (0.2 μCi), 1% DMSO, and 0 to 100 μMof the compound to be tested are incubated together for 10 minutes atroom temperature. The reaction is then terminated by the addition of 10μL 0.25 M ethylenediaminetetraacetate (EDTA) pH 7. Using a multichanneldispenser (LAB SYSTEMS, USA), an aliquot of 20 μL is applied to a PVDF(=polyvinyl difluoride) Immobilon P membrane (Millipore, Bedford, USA),through a Gibco-BRL microtiter filter manifold and connected to avacuum. Following complete elimination of the liquid, the membrane iswashed 4 times successively in a bath containing 0.5% phosphoric acid(H₃PO₄) and once with ethanol, incubated for 10 minutes each time whileshaking, then mounted in a Hewlett Packard TopCount Manifold and theradioactivity measured after the addition of 10 μL Microscint®(β-scintillation counter liquid). IC₅₀-values are determined by linearregression analysis of the percentages for the inhibition of eachcompound in at least four concentrations (as a rule 0.01, 0.1, 1.0 and10 μmol). The IC₅₀-values that can be found with compounds of formula Iare in the range of 1 to 10'000 nM, preferably in the range of 1 to 100nM.

The inhibition of VEGF-induced KDR-receptor autophosphorylation can beconfirmed with a further in vitro experiment in cells: transfected CHOcells, which permanently express human VEGF receptor (KDR), are seededin complete culture medium with 10% fetal calf serum (FCS) in swellcell-culture plates and incubated at 37° C. under 5% CO₂ until they showabout 80% confluency. The compounds to be tested are then diluted inculture medium (without FCS, with 0.1% bovine serum albumin) and addedto the cells. (Controls comprise medium without test compounds). Aftertwo hours of incubation at 37° C., recombinant VEGF is added; the finalVEGF concentration is 20 ng/mL). After a further five minute incubationat 37° C., the cells are washed twice with ice-cold PBS(phosphate-buffered saline) and immediately lysed in 100 μL lysis bufferper well. The lysates are then centrifuged to remove the cell nuclei,and the protein concentrations of the supernatants are determined usinga commercial protein assay (BIORAD). The lysates can then either beimmediately used or, if necessary, stored at −20° C.

A sandwich ELISA is carried out to measure the KDR-receptorphosphorylation: a monoclonal antibody to KDR (for example Mab1495.12.14) is immobilized on black ELISA plates (OptiPlate™ HTRF-96from Packard). The plates are then washed and the remaining freeprotein-binding sites are saturated with 1% BSA in PBS. The cell lysates(20 μg protein per well) are then incubated in these plates overnight at4° C. together with an anti-phosphotyrosine antibody coupled withalkaline phosphatase (PY20:AP from Transduction Laboratories). Theplates are washed again and the binding of the antiphosphotyrosineantibody to the captured phosphorylated receptor is then demonstratedusing a luminescent AP substrate (CDP-Star, ready to use, with EmeraldII; TROPIX). The luminescence is measured in a Packard Top CountMicroplate Scintillation Counter (Top Count). The difference between thesignal of the positive control (stimulated with VEGF) and that of thenegative control (not stimulated with VEGF) corresponds to VEGF-inducedKDR-receptor phosphorylation (=100%). The activity of the testedsubstances is calculated as % inhibition of VEGF-induced KDR-receptorphosphorylation, wherein the concentration of substance that induceshalf the maximum inhibition is defined as the ED50 (effective dose for50% inhibition). Compounds of formula I here preferably show ED50 valuesin the range of 0.25 nM to 1000 nM, preferably 0.25 to 250 nM.

A compound of formula I or a N-oxide thereof inhibits to varying degreesalso other tyrosine kinases involved in signal transduction which aremediated by trophic factors, for example Bcr-Abl and Abl kinase, Arg,kinases from the Src family, especially c-Src kinase, Lck, and Fyn; alsokinases of the EGF family, for example, c-erbB2 kinase (HER-2), c-erbB3kinase, c-erbB4 kinase; insulin-like growth factor receptor kinase(IGF-1 kinase), especially members of the PDGF-receptor tyrosine kinasefamily, such as PDGF-receptor kinase, CSF-1-receptor kinase,Kit-receptor kinase and VEGF-receptor kinase; and also serine/threoninekinases, all of which play a role in growth regulation andtransformation in mammalian cells, including human cells.

The inhibition of c-erbB2 tyrosine kinase (HER-2) can be measured, forexample, in the same way as the inhibition of EGF-R protein kinase,using known procedures.

On the basis of these studies, a compound of formula I according to theinvention shows therapeutic efficacy especially against disordersdependent on protein kinase, especially proliferative diseases.

On the basis of their efficacy as inhibitors of VEGF-receptor tyrosinekinase activity, the compounds of the formula I primarily inhibit thegrowth of blood vessels and are thus, for example, effective against anumber of diseases associated with deregulated angiogenesis, especiallydiseases caused by ocular neovascularisation, especially retinopathies,such as diabetic retinopathy or age-related macula degeneration,psoriasis, haemangioblastoma, such as haemangioma, mesangial cellproliferative disorders, such as chronic or acute renal diseases, e.g.diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathy syndromes or transplant rejection, or especiallyinflammatory renal disease, such as glomerulonephritis, especiallymesangioproliferative glomerulonephritis, haemolytic-uraemic syndrome,diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterialrestenosis, autoimmune diseases, diabetes, endometriosis, chronicasthma, and especially neoplastic diseases (solid tumors, but alsoleukemias and other “liquid tumors”, especially those expressing c-kit,KDR, Flt-1 or Flt-3), such as especially breast cancer, cancer of thecolon, lung cancer (especially small-cell lung cancer), cancer of theprostate or Kaposi's sarcoma. A compound of formula I (or an N-oxidethereof) inhibits the growth of tumours and is especially suited topreventing the metastatic spread of tumors and the growth ofmicrometastases.

A compound of formula I can be administered alone or in combination withone or more other therapeutic agents, possible combination therapytaking the form of fixed combinations or the administration of acompound of the invention and one or more other therapeutic agents beingstaggered or given independently of one another, or the combinedadministration of fixed combinations and one or more other therapeuticagents. A compound of formula I can besides or in addition beadministered especially for tumor therapy, such as leukaemia therapy, incombination with chemotherapy, radiotherapy, immunotherapy, surgicalintervention, or a combination of these. Long-term therapy is equallypossible as is adjuvant therapy in the context of other treatmentstrategies, as described above. Other possible treatments are therapy tomaintain the patient's status after tumor regression, or evenchemopreventive therapy, for example in patients at risk.

Therapeutic agents for possible combination are especially one or morecytostatic or cytotoxic compounds, for example a chemotherapeutic agentor several selected from the group comprising indarubicin, cytarabine,interferon, hydroxyurea, bisulfan, or an inhibitor of polyaminebiosynthesis, an inhibitor of protein kinase, especially ofserine/threonine protein kinase, such as protein kinase C, or oftyrosine protein kinase, such as epidermal growth factor receptortyrosine kinase, a cytokine, a negative growth regulator, such as TGF-βor IFN-β, an aromatase inhibitor, a classical cytostatic, and aninhibitor of the interaction of an SH2 domain with a phosphorylatedprotein.

A compound according to the invention is not only for the (prophylacticand preferably therapeutic) management of humans, but also for thetreatment of other warm-blooded animals, for example of commerciallyuseful animals, for example rodents, such as mice, rabbits or rats, orguinea-pigs. Such a compound may also be used as a reference standard inthe test systems described above to permit a comparison with othercompounds.

In general, the invention relates also to the use of a compound offormula I or a N-oxide thereof for the inhibition of tyrosine kinaseactivity, either in vitro or in vivo.

With the groups of preferred compounds of formula I and N-oxides thereofmentioned hereinafter, definitions of substituents from the generaldefinitions mentioned hereinbefore may reasonably be used, for example,to replace more general definitions with more specific definitions orespecially with definitions characterized as being preferred.

In particular, the invention relates to compounds of formula I, wherein

R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, or phenyl-lower alkyl;

R₂ represents hydrogen, lower alkyl, optionally substituted by one ortwo identical or different radicals R₃, cycloalkyl, benzcycloalkyl,heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl groupcomprising one, two or three nitrogen atoms or one sulfur atom, whicharyl and heteroaryl groups in each case are unsubstituted or mono- orpolysubstituted;

and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an arylgroup, furanoyl, thienoyl, or a mono- or bicyclic heteroaryl groupcomprising one, two or three ring nitrogen atoms, zero or one ringoxygen atom and zero or one ring sulphur atom, which aryl and heteroarylgroups in each case are unsubstituted or mono- or polysubstituted;

or wherein R₁ and R₂ together represent alkylene with four or fivecarbon atoms, optionally mono- or disubstituted by lower alkyl,cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- ordisubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylenewith four or five carbon atoms in the alkylene group; oxaalkylene withone oxygen and three or four carbon atoms, or azaalkylene with onenitrogen and three or four carbon atoms wherein nitrogen isunsubstituted or substituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl,N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, loweralkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, orpyrazinyl;

R₄ represents hydrogen, lower alkyl, or halogen;

and a N-oxide or a pharmaceutically acceptable salt of such a compound.

More particular, the invention relates to compounds of formula I,wherein

R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;

R₂ represents hydrogen, lower alkyl, optionally substituted by one ortwo identical or different radicals R₃, cyclopentyl, benzcyclopentyl,cylcohexyl, pyrrolidinyl, oxazolinyl, piperidinyl, N-substitutedpiperidinyl, morpholinyl, azepinyl, oxo-azepinyl, oxazepinyl, phenyl,naphthalinyl, tetrahydronaphthalinyl or a mono- or bicyclic heteroarylgroup comprising one or two nitrogen atoms, which phenyl, naphthalinyland heteroaryl groups in each case are unsubstituted or mono- orpolysubstituted, thienyl, or lower alkoxycarbonyl-lower alkylthienyl;

and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, lower alkylamino, di-lower alkylamino, phenylamino, N-loweralkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino,morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl,furyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- orbicyclic heteroaryl group comprising one or two nitrogen atoms, whichphenyl, naphthalinyl and heteroaryl group are unsubstituted or mono- orpolysubstituted;

or wherein R₁ and R₂ together represent alkylene with four or fivecarbon atoms, optionally mono- or disubstituted by lower alkyl,cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- ordisubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylenewith four or five carbon atoms in the alkylene group; oxaalkylene withone oxygen and four carbon atoms; or azaalkylene with one nitrogen andfour carbon atoms wherein nitrogen is unsubstituted or substituted bylower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl,carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstitutedcarbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl,substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;

R₄ represents hydrogen, lower alkyl, or halogen;

and a N-oxide or a pharmaceutically acceptable salt of such a compound.

More particular, the invention relates to compounds of formula I,wherein

R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;

R₂ represents hydrogen; lower alkyl, optionally substituted by oneradical R₃, by two phenyl groups, by two lower alkoxycarbonyl groups, byphenyl and lower alkoxycarbonyl, or by hydroxyphenyl and loweralkoxycarbonyl; cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl;oxazolinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl;N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxo-azepinyl;oxazepinyl; phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- orbicyclic heteroaryl group comprising one or two nitrogen atoms, whichphenyl, naphthalinyl and heteroaryl groups in each case areunsubstituted or substituted by one or two substituents selected fromthe group consisting of lower alkyl, trifluoro-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, loweralkylamino-lower alkyl, di-lower alkylamino-lower alkyl,N-cyclohexyl-N-lower alkylamino-lower alkyl, loweralkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-loweralkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy,trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy,benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- ordisubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, 1H-imidazolyl, mono- or di-loweralkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-loweralkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl,phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio,phenylthio, phenyl, pyridyl, halogenyl, or benzoyl; thienyl; or loweralkoxycarbonyl-lower alkylthienyl; and

R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, carbamoyl mono-or disubstituted by loweralkyl, phenyl or lower alkylene, amino, lower alkylamino, di-loweralkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino,oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino,cycloalkyl, heterocyclyl, furyl; phenyl, naphthalinyl,tetrahydronaphthalinyl, or a mono- or bicyclic heteroaryl groupcomprising one or two nitrogen atoms, which phenyl, naphthalinyl andheteroaryl group is unsubstituted or substituted by one or twosubstituents selected from the group consisting of lower alkyl,trifluoro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, loweralkoxy, trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy,lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino,benzoylamino, amino mono- or disubstituted by lower alkyl, byhydroxy-lower alkyl or by loweralkoxy-lower alkyl, pyrrolidino,piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-loweralkoxycarbonylpiperazino, phenyl, pyridyl, 1H-imidazolyl, loweralkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl,lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio,halogenyl, or benzoyl;

or wherein R₁ and R₂ together represent alkylene with four or fivecarbon atoms, optionally mono- or disubstituted by lower alkyl,cycloalkyl, phenyl, hydroxy, lower alkoxy, amino, benzoylamino,piperidino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four orfive carbon atoms in the alkylene group; oxaalkylene with one oxygen andfour carbon atoms; or azaalkylene with one nitrogen and four carbonatoms wherein nitrogen is unsubstituted or substituted by lower alkyl,phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-loweralkyl, carbamoyl-lower alkyl, carbamoyl-lower alkyl N-mono- orN,N-disubstituted by lower alkyl, phenyl, lower alkylene or oxa-loweralkylene, cycloalkyl, lower alkoxycarbonyl, phenyl, methoxyphenyl,trifluoromethylphenyl, trifluoromethoxyphenyl, pyridinyl, pyrimidinyl,or pyrazinyl;

R₄ represents hydrogen or lower alkyl;

and a N-oxide or a pharmaceutically acceptable salt of such a compound.

In a preferred group of compounds of formula I,

R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, orbenzyl;

R₂ represents lower alkyl, optionally substituted by one radical R₃, bytwo phenyl groups, by two lower alkoycarbonyl groups, by phenyl andlower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl;cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; piperidinyl;N-lower alkylpiperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl;morpholinyl; azepinyl; oxoazepinyl; phenyl; naphthalinyl;tetrahydronaphthalinyl; pyridyl; lower alkyl-pyridyl; quinolinyl;thienyl; lower alkoxycarbonylmethylthienyl; or phenyl substituted by oneor two substituents selected from the group consisting of lower alkyl,trifluoro-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, loweralkylamino-lower alkyl, di-lower alkylamino-lower alkyl,N-cyclohexyl-N-lower alkylamino-lower alkyl, loweralkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-loweralkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy,trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy,benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, loweralkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- ordisubstituted by lower alkyl, by hydroxy-lower alkyl or byloweralkoxy-lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl,pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino,morpholino, sulfamoyl, lower alkylsulfonyl, phenyl, pyridyl, halogenyl,or benzoyl;

and R₃ represents hydroxy, lower alkoxy, lower alkanoyloxy, benzoyloxy,carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino,di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino,pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino,oxoimidazolino, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl,phenyl, naphthalinyl, tetrahydronaphthalinyl, furyl, a mono- or bicyclicheteroaryl group comprising one or two nitrogen atoms, which heteroarylgroup is unsubstituted or mono- or disubstituted by lower alkyl, hydroxyand lower alkoxy, or phenyl substituted by one or two substituentsselected from the group consisting of lower alkyl, trifluoro-loweralkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy,trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino,amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl orby loweralkoxy-lower alkyl, pyrrolidino, piperidino, morpholino,piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino,phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl,lower alkylsulfonyl, halogenyl, or benzoyl;

or wherein R₁ and R₂ together represent alkylene with four or fivecarbon atoms, optionally mono- or disubstituted by phenyl, hydroxy,amino, benzoylamino, or piperidino; benzalkylene with four or fivecarbon atoms in the alkylene group; oxaalkylene with one oxygen and fourcarbon atoms; or azaalkylene with one nitrogen and four carbon atomswherein nitrogen is unsubstituted or substituted by lower alkyl,phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-loweralkyl, pyrrolidinocarbonyl-lower alkyl, morpholinocarbonyl-lower alkyl,cyclopentyl, lower alkoxycarbonyl, phenyl, methoxyphenyl,trifluoromethylphenyl, pyridinyl; pyrimidinyl, or pyrazinyl;

R₄ represents hydrogen or methyl;

and a N-oxide or a pharmaceutically acceptable salt of such a compound.

A specially preferred group of compounds comprises compounds of formulaI wherein

R₁ represents hydrogen, and

R₂ represents phenyl substituted by trifluoromethyl, especially3-trifluoromethylphenyl, and optionally a further substituent selectedfrom the group consisting of hydroxy-lower alkyl, e.g.1-hydroxy-1-methylethyl, lower alkylamino, e.g. methyl- or ethylamino,hydroxy-lower alkylamino, e.g. 2-hydroxy-1-propylamino or2-hydroxy-2-propylamino, di-lower alkylamino, e.g. diethylamino,1H-imidazolyl, lower alkyl-1H-imidazolyl, e.g. 2- or4-methyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, e.g.methylcarbamoyl, pyrrolidino, piperidino, piperazino, loweralkylpiperazino, e.g. 4-methylpiperazino, morpholino, lower alkoxy, e.g.methoxy, fluoro-lower alkoxy, e.g. trifluoromethoxy or2,2,2-trifluoroethoxy, phenyl, pyridyl, e.g. 2-, 3- or 4-pyridyl, andhalogenyl, e.g.chloro or fluoro;

R₄ represents methyl;

and a N-oxide or a pharmaceutically acceptable salt of such a compound.

One preferred embodiment of the invention relates to compounds offormula I wherein

R₁ is hydrogen,

R₂ represents phenyl which is mono- or disubstituted by imidazol-loweralkoxy, lower alkyl amino, trifluoromethyl, hydroxy lower alkyl amino,bis-(lower alkoxy lower alkyl) amino, lower alkyl piperazinyl,piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridyl, imidazolylwhich is unsubstituted or mono- or disubstituted by lower alkyl orN-lower alkyl carbamoyl;

R₄ is lower alkyl;

and to the N-oxides and pharmaceutically acceptable salts of suchcompounds.

Particularly preferred are the compounds of the Examples.

Other compounds which are particularly preferred are:

-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzanilide,-   4-Methyl-N-(3-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   2(R)- and    2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamino]propanoic    acid,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(8-quinolinyl)benzamide,-   4-Methyl-3-[[(4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-[trifluoromethoxy]phenyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidinoethyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-pyrrolidinophenyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(1-[2-pyrimidinyl]-4-piperidinyl)benzamide,-   N-(4-Di-[2-methoxyethyl]amino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-[1H-Imidazolyl]-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidino-5-trifluoromethylphenyl)benzamide,-   N-(3,4-difluorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylbenzyl)benzamide,-   4-Methyl-3-[[4(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylphenyl)benzamide,-   N-(3-Chloro-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Dimethylaminobutyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[4-(4-methyl-1-piperazinyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethylphenyl]benzamide,-   4-Methyl-N-[4-(2-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-(4-phenyl-3-trifluoromethylphenyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[4-(4-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   Methyl 2(R)- and    2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamio]-3-[4-hydroxyphenyl]propanoate,-   N-[2-(N-Cyclohexyl-N-methylaminomethyl)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-[3-[2-(1H-Imidazolyl)ethoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[3-morpholino-5-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-pyrrolidino-3-trifluoromethylphenyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-piperidino-3-trifluoromethylphenyl)benzamide,-   4-Methyl-N-[4-morpholino-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Ethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethoxyphenyl)benzamide,-   N-[4-(2-Hydroxypropylamino)-3-trifluoromethylphenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Diethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(3-pyridinyl)-5-trifluorophenyl]benzamide,-   N-[3-[3-(1H-Imidazolyl)propoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N[4-(3-pyridinyl)-3-trifluorophenyl]benzamide,-   4-Methyl-N-[3-(4-methyl-1-piperazinyl)-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[3-methylcarbamoyl-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[3-methylcarbamoyl-5-morpholino]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide.

Further compounds which are particularly preferred are:

-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]-phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(diethylamino)-3-(trifluoromethyl)phenyl]benzamide,-   (±)-4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N[4-[(2-hydroxypropyl)amino]-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N[4-phenyl-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonyl]phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(3-pyridinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N[5-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]benzamide,    and-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide.

The invention relates also to4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid and to3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid; intermediates forthe formation of the preferred amides of the invention.

Especially, the invention relates to the use of a compound of formula Ior of a N-oxide or a possible tautomer thereof or of a pharmaceuticallyacceptable salt of such a compound for the preparation of apharmaceutical composition for the treatment of a disease which respondsto an inhibition of protein kinase activity, wherein the disease is aneoplastic disease.

More particularly, the invention relates to the use of a compound of theformula I or of a N-oxide or a possible tautomer thereof; or of apharmaceutically acceptable salt of such a compound for the preparationof a pharmaceutical composition for the treatment of leukaemia whichresponds to an inhibition of the Abl tyrosine kinase activity.

Furthermore, the invention provides a method for the treatment of adisease which responds to an inhibition of protein kinase activity,which comprises administering a compound of formula I or a N-oxide or apharmaceutically acceptable salt thereof, wherein the radicals andsymbols have the meanings as defined above, in a quantity effectiveagainst said disease, to a warm-blooded animal requiring such treatment.

A compound of the invention may be prepared by processes that, thoughnot applied hitherto for the new compounds of the present invention, areknown per se, especially a process characterized in that for thesynthesis of a compound of the formula I wherein the symbols R₁, R₂ andR₄ are as defined for a compound of the formula I, a4-R₄-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid of formula II

wherein R₄ is as defined for a compound of formula I, or a derivativethereof wherein the carboxy group —COOH is in activated form, is reactedwith an amine of the formula IIIR₁—NH—R₂  (III)wherein R₁ and R₂ are as defined for a compound of the formula I,optionally in the presence of a dehydrating agent and an inert baseand/or a suitable catalyst, and optionally in the presence of an inertsolvent;where the above starting compounds II and III may also be present withfunctional groups in protected form if necessary and/or in the form ofsalts, provided a salt-forming group is present and the reaction in saltform is possible;any protecting groups in a protected derivative of a compound of theformula I are removed;and, if so desired, an obtainable compound of formula I is convertedinto another compound of formula I or a N-oxide thereof, a free compoundof formula I is converted into a salt, an obtainable salt of a compoundof formula I is converted into the free compound or another salt, and/ora mixture of isomeric compounds of formula I is separated into theindividual isomers.Detailed Description of the Process:

A derivative of the compound of formula II wherein the carboxy group isin activated form is especially a reactive ester, a reactive anhydrideor a reactive cyclic amide.

Reactive esters of the acid of formula II are especially estersunsaturated at the linking carbon atom of the esterifying radical, forexample esters of the vinyl ester type, such as actual vinyl esters(obtainable, for example, by transesterification of a correspondingester with vinyl acetate; activated vinyl ester method), carbamoylvinylesters (obtainable, for example, by treatment of the corresponding acidwith an isoxazolium reagent; 1,2-oxazolium or Woodward method), or1-lower alkoxyvinyl esters (obtainable, for example, by treatment of thecorresponding acid with a lower alkoxyacetylene; ethoxyacetylenemethod), or esters of the amidino type, such as N,N′-disubstitutedamidino esters (obtainable, for example, by treatment of thecorresponding acid with a suitable N,N′-disubstituted carbodiimide, forexample N,N′-dicyclohexylcarbodiimide; carbodiimide method), orN,N-disubstituted amidino esters (obtainable, for example, by treatmentof the corresponding acid with an N,N-disubstituted cyanamide; cyanamidemethod), suitable aryl esters, especially phenyl esters suitablysubstituted by electron-attracting substituents (obtainable, forexample, by treatment of the corresponding acid with a suitablysubstituted phenol, for example 4-nitrophenol, 4-methylsulfonyl-phenol,2,4,5-trichlorophenol, 2,3,4,5,6-pentachloro-phenol or4-phenyldiazophenol, in the presence of a condensation agent, such asN,N′-dicyclohexyl-carbodiimide; activated aryl esters method),cyanomethyl esters (obtainable, for example, by treatment of thecorresponding acid with chloroacetonitrile in the presence of a base;cyanomethyl esters method), thio esters, especially unsubstituted orsubstituted, for example nitro-substituted, phenylthio esters(obtainable, for example, by treatment of the corresponding acid withunsubstituted or substituted, for example nitro-substituted,thiophenols, inter alia by the anhydride or carbodiimide method;activated thiol esters method), amino or amido esters (obtainable, forexample, by treatment of the corresponding acid with an N-hydroxy-aminoor N-hydroxy-amido compound, for example N-hydroxy-succinimide,N-hydroxy-piperidine, N-hydroxy-phthalimide or 1-hydroxy-benzotriazole,for example by the anhydride or carbodiimide method; activated N-hydroxyesters method), or silyl esters (which are obtainable, for example, bytreatment of the corresponding acid with a silylating agent, for examplehexamethyl disilazane, and react readily with hydroxy groups but notwith amino groups).

Anhydrides of the acid of formula II may be symmetric or preferablymixed anhydrides of that acid, for example anhydrides with inorganicacids, such as acid halides, especially acid chlorides (obtainable, forexample, by treatment of the corresponding acid with thionyl chloride,phosphorus pentachloride or oxalyl chloride; acid chloride method),azides (obtainable, for example, from a corresponding acid ester via thecorresponding hydrazide and treatment thereof with nitrous acid; azidemethod), anhydrides with carbonic acid semiderivatives, such ascorresponding esters, for example carbonic acid lower alkyl semiesters(obtainable, for example, by treatment of the corresponding acid withhaloformic, such as chloroformic, acid lower alkyl esters or with a1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixedO-alkylcarbonic acid anhydrides method), or anhydrides withdihalogenated, especially dichlorinated, phosphoric acid (obtainable,for example, by treatment of the corresponding acid with phosphorusoxychloride; phosphorus oxychloride method), or anhydrides with organicacids, such as mixed anhydrides with organic carboxylic acids(obtainable, for example, by treatment of the corresponding acid with anunsubstituted or substituted lower alkane- or phenylalkane-carboxylicacid halide, for example phenylacetic acid chloride, pivalic acidchloride or trifluoroacetic acid chloride; mixed carboxylic acidanhydrides method), with organic sulfonic acids (obtainable, forexample, by treatment of a salt, such as an alkali metal salt, of thecorresponding acid, with a suitable organic sulfonic acid halide, suchas lower alkane- or aryl-, for example methane- or p-toluene-sulfonicacid chloride; mixed sulfonic acid anhydrides method), or with organicphosphonic acids (obtainable, for example, by treatment of thecorresponding acid with a suitable organic phosphonic anhydride orphosphonic cyanide; mixed phosphonic acid anhydrides methhod), andsymmetric anhydrides (obtainable, for example, by condensation of thecorresponding acid in the presence of a carbodiimide or of1-diethylaminopropyne; symmetric anhydrides method).

Suitable cyclic amides are especially amides with five-membereddiazacycles of aromatic character, such as amides with imidazoles, forexample imidazole (obtainable, for example, by treatment of thecorresponding acid with N,N′-carbonyldiimidazole; imidazolide method),or pyrazoles, for example 3,5-dimethyl-pyrazole (obtainable, forexample, by way of the acid hydrazide by treatment with acetylacetone;pyrazolide method).

Derivatives of the acid of formula II wherein the carboxy group is inactivated form are preferably formed in situ. For example,N,N′-disubstituted amidino esters can be formed in situ by reacting amixture of the acid of formula II and the amine of formula III in thepresence of a suitable N,N-disubstituted carbodiimide, for exampleN,N′-dicyclohexylcarbodiimide. Reactive mixed anhydrides of the acid offormula II with an organic phosphonic acid may be formed in situ byreaction with e.g. propylphosphonic anhydride or diethylcyanophosphonatein the presence of suitable base, preferably a tertiary amine, e.g.triethylamine or dimethylaminopyridine.

The reaction can be carried out in a manner known per se, the reactionconditions being dependent especially on whether, and if so how, thecarboxy group of the carboxylic acid of formula II has been activated,usually in the presence of a suitable solvent or diluent or of a mixturethereof and, if necessary, in the presence of a condensation agent,which, for example when the carboxy group participating in the reactionis in the form of an anhydride, may also be an acid-binding agent, withcooling or heating, for example in a temperature range fromapproximately −30° C. to approximately +150° C., especiallyapproximately from 0° C. to +100° C., preferably from room temperature(approx. +20° C.) to +70° C., in an open or closed reaction vesseland/or in the atmosphere of an inert gas, for example nitrogen.Customary condensation agents are, for example, carbodiimides, forexample N,N′-diethyl-, N,N′-dipropyl-, N,N′-dicyclohexyl- orN-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide, suitable carbonylcompounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds,for example 2-ethyl-5-phenyl-1,2-oxazolium 3′-sulfonate and2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.Customary acid-binding condensation agents are, for example, alkalimetal carbonates or hydrogen carbonates, for example sodium or potassiumcarbonate or hydrogen carbonate (customarily together with a sulfate),or organic bases, such as, customarily, pyridine or triethylamine, orsterically hindered tri-lower alkylamines, for exampleN,N-diisopropyl-N-ethyl-amine.

In a preferred variant, the carboxylic acid of formula II is reactedwith an amine of formula III in a suitable solvent, such as e.g.N,N-dimethylformamide, in the presence of propyl-phosphonic anhydride ordiethylcyanophosphanate and triethylamine, between 1 and 48 hours atbetween 0° C. and around 50° C., preferably at room temperature.

Protecting Groups

If one or more other functional groups, for example carboxy, hydroxy,amino, or mercapto, are or need to be protected in a compound of formulaIII, because they should not take part in the reaction, these are suchgroups as are usually used in the synthesis of amides, in particularpeptide compounds, and also of cephalosporins and penicillins, as wellas nucleic acid derivatives and sugars.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they lend themselves readily, i.e. withoutundesired secondary reactions, to removal, typically by solvolysis,reduction, photolysis or also by enzyme activity, for example underconditions analogous to physiological conditions, and that they are notpresent in the end-products. The specialist knows, or can easilyestablish, which protecting groups are suitable with the reactionsmentioned hereinabove and hereinafter.

The protection of such functional groups by such protecting groups, theprotecting groups themselves, and their removal reactions are describedfor example in standard reference books for peptide synthesis as citedhereinbefore, and in special books on protective groups such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973, in “Methoden der organischen Chemie” (Methods oforganic chemistry), Houben-Weyl, 4th edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart 1974, and in T. W. Greene, “Protective Groups inOrganic Synthesis”, Wiley, N.Y.

Additional Process Steps

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more of the protecting groups mentioned hereinaboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

Salts of a compound of formula I with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds offormula I may thus be obtained by treatment with an acid or with asuitable anion exchange reagent.

Salts can usually be converted to free compounds, e.g. by treating withsuitable basic agents, for example with alkali metal carbonates, alkalimetal hydrogencarbonates, or alkali metal hydroxides, typicallypotassium carbonate or sodium hydroxide.

Stereoisomeric mixtures, e.g. mixtures of diastereomers, can beseparated into their corresponding isomers in a manner known per se bymeans of suitable separation methods. Diastereomeric mixtures forexample may be separated into their individual diastereomers by means offractionated crystallization, chromatography, solvent distribution, andsimilar procedures. This separation may take place either at the levelof a starting compound or in a compound of formula I itself. Enantiomersmay be separated through the formation of diastereomeric salts, forexample by salt formation with an enantiomer-pure chiral acid, or bymeans of chromatography, for example by HPLC, using chromatographicsubstrates with chiral ligands.

A compound of the formula I wherein R₁ is hydrogen can be converted tothe respective compound wherein R₁ is lower alkyl by reaction e.g. witha diazo lower alkyl compound, especially diazomethane, in an inertsolvent, preferably in the presence of a noble metal catalyst,especially in dispersed form, e.g. copper, or a noble metal salt, e.g.copper(I)-chloride or copper(II)-sulfate. Also reaction with loweralkylhalogenides is possible, or with other leaving group carrying loweralkanes, e.g. lower alkyl alcohols esterified by a strong organicsulfonic acid, such as a lower alkanesulfonic acid (optionallysubstituted by halogen, such as fluoro), an aromatic sulfonic acid, forexample unsubstituted or substituted benzenesulfonic acid, thesubstituents preferably being selected from lower alkyl, such as methyl,halogen, such as bromo, and/or nitro, e.g. esterified by methanesulfonicacid, or p-toluene sulfonic acid. The alkylation takes place under usualconditions for alkylation of amides, especially in aqueous solutionand/or in the presence of polar solvents, typically alcohols, forexample methanol, ethanol, isopropanol, or ethylene glycol, or dipolaraprotic solvents, e.g. tetrahydrofuran, dioxane, or dimethylformamide,where applicable in the presence of acidic or basic catalysts, generallyat temperatures from about 0° C. to the boiling temperature of thecorresponding reaction mixture, preferably between 20° C. and refluxtemperature, if necessary under increased pressure, e.g. in a sealedtube, and/or under inert gas, typically nitrogen or argon.

It should be emphasized that reactions analogous to the conversionsmentioned in this chapter may also take place at the level ofappropriate intermediates.

General Process Conditions

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralisiing agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at roomtemperature, at −20 to 40° C. or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder argon or nitrogen.

Salts may be present in all starting compounds and transients, if thesecontain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

At all reaction stages, isomeric mixtures that occur can be separatedinto their individual isomers, e.g. diastereomers or enantiomers, orinto any mixtures of isomers, e.g. racemates or diastereomeric mixtures.

The invention relates also to those forms of the process in which onestarts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described hereinabove as preferred, particularly as especiallypreferred, primarily preferred, and/or preferred above all.

In the preferred embodiment, a compound of formula I is preparedaccording to or in analogy to the processes and process steps defined inthe Examples.

The compounds of formula I, including their salts, are also obtainablein the form of hydrates, or their crystals can include for example thesolvent used for crystallization (present as solvates).

Pharmaceutical Preparations, Methods, and Uses

The present invention relates furthermore to a method for the treatmentof a neoplastic disease which responds to an inhibition of a proteinkinase activity, which comprises administering a compound of formula Ior a N-oxide or a pharmaceutically acceptable salt thereof, wherein theradicals and symbols have the meanings as defined above for formula I,in a quantity effective against said disease, to a warm-blooded animalrequiring such treatment.

In particular the invention relates to a method for the treatment ofleukaemia which responds to an inhibition of the Abl tyrosine kinaseactivity, which comprises administering a compound of formula I or aN-oxide or a pharmaceutically acceptable salt thereof, wherein theradicals and symbols have the meanings as defined above for formula I,in a quantity effective against said leukaemia, to a warm-blooded animalrequiring such treatment.

The present invention relates also to pharmaceutical compositions thatcomprise a compound of formula I or a N-oxide thereof as activeingredient and that can be used especially in the treatment of thediseases mentioned at the beginning. Compositions for enteraladministration, such as nasal, buccal, rectal or, especially, oraladministration, and for parenteral administration, such as intravenous,intramuscular or subcutaneous administration, to warm-blooded animals,especially humans, are especially preferred. The compositions comprisethe active ingredient alone or, preferably, together with apharmaceutically acceptable carrier. The dosage of the active ingredientdepends upon the disease to be treated and upon the species, its age,weight, and individual condition, the individual pharmacokinetic data,and the mode of administration.

The present invention relates especially to pharmaceutical compositionsthat comprise a compound of formula I, a tautomer, a N-oxide or apharmaceutically acceptable salt, or a hydrate or solvate thereof, andat least one pharmaceutically acceptable carrier.

The invention relates also to pharmaceutical compositions for use in amethod for the prophylactic or especially therapeutic management of thehuman or animal body, to a process for the preparation thereof(especially in the form of compositions for the treatment of tumors) andto a method of treating tumor diseases, especially those mentionedhereinabove.

The invention relates also to processes and to the use of compounds offormula I or N-oxides thereof for the preparation of pharmaceuticalpreparations which comprise compounds of formula I or N-oxides thereofas active component (active ingredient).

In the preferred embodiment, a pharmaceutical preparation is suitablefor administration to a warm-blooded animal, especially humans orcommercially useful mammals suffering from a disease responsive to aninhibition of the Abl tyrosine kinase, for example chronic myelogenousleukaemia (CML), and comprises an effective quantity of a compound offormula I or N-oxides thereof for the inhibition of the Bcr-Abl fusionprotein, or a pharmaceutically acceptable salt thereof, if salt-forminggroups are present, together with at least one pharmaceuticallyacceptable carrier.

A pharmaceutical composition for the prophylactic or especiallytherapeutic management of neoplastic and other proliferative diseases ofa warm-blooded animal, especially a human or a commercially usefulmammal requiring such treatment, especially suffering from such adisease, comprising as active ingredient in a quantity that isprophylactically or especially therapeutically active against the saiddiseases a novel compound of formula I or N-oxides thereof, is likewisepreferred.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories, or capsules. Further dosage forms are, for example,ointments, creams, pastes, foams, tinctures, sprays, etc. Examples arecapsules containing from about 0.05 g to about 1.0 g active ingredient.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilizing processes.

Preference is given to the use of solutions of the active ingredient,and also suspensions or dispersions, especially isotonic aqueoussolutions, dispersions or suspensions which, for example in the case oflyophilized compositions comprising the active ingredient alone ortogether with a carrier can be made up before use. The pharmaceuticalcompositions may be sterilized and/or may comprise excipients, forexample preservatives, stabilizers, wetting agents and/or emulsifiers,solubilizers, salts for regulating osmotic pressure and/or buffers andare prepared in a manner known per se, for example by means ofconventional dissolving and lyophilizing processes. The said solutionsor suspensions may comprise viscosity-increasing agents or solubilizers.

Suspensions in oil comprise as the oil component the vegetable,synthetic, or semi-synthetic oils customary for injection purposes. Inrespect of such, special mention may be made of liquid fatty acid estersthat contain as the acid component a long-chained fatty acid having from8 to 22 carbon atoms. The alcohol component of these fatty acid estershas a maximum of 6 carbon atoms and is a monovalent or polyvalent, forexample a mono-, di- or trivalent, alcohol, especially glycol andglycerol.

Pharmaceutical compositions for oral administration can be obtained, forexample, by combining the active ingredient with one or more solidcarriers, if desired granulating a resulting mixture, and processing themixture or granules, if desired or necessary, by the inclusion ofadditional excipients, to form tablets or tablet cores.

Suitable carriers are especially fillers, such as sugars, cellulosepreparations, and/or calcium phosphates, and also binders, such asstarches, and/or polyvinylpyrrolidone, and/or, if desired,disintegrators. Additional excipients are especially flow conditionersand lubricants.

Tablet cores can be provided with suitable, optionally enteric, coatingsthrough the use of, inter alia, concentrated sugar solutions which maycomprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations.

Pharmaceutical compositions for oral administration also include hardcapsules consisting of gelatin, and also soft, sealed capsulesconsisting of gelatin and a plasticizer. The hard capsules may containthe active ingredient in the form of granules, for example in admixturewith fillers, binders, and/or glidants, and optionally stabilizers. Insoft capsules, the active ingredient is preferably dissolved orsuspended in suitable liquid excipients, to which stabilizers anddetergents may also be added.

Pharmaceutical compositions suitable for rectal administration are, forexample, suppositories that consist of a combination of the activeingredient and a suppository base.

For parenteral administration, aqueous solutions of an active ingredientin water-soluble form, for example of a water-soluble salt, or aqueousinjection suspensions that contain viscosity-increasing substances, forexample sodium carboxymethylcellulose, sorbitol and/or dextran, and, ifdesired, stabilizers, are especially suitable. The active ingredient,optionally together with excipients, can also be in the form of alyophilizate and can be made into a solution before parenteraladministration by the addition of suitable solvents.

Solutions such as are used, for example, for parenteral administrationcan also be employed as infusion solutions.

Preferred preservatives are, for example, antioxidants, such as ascorbicacid, or microbicides, such as sorbic acid or benzoic acid.

The invention relates likewise to a process or a method for thetreatment of one of the pathological conditions mentioned hereinabove,especially a disease which responds to an inhibition of a tyrosinekinase, especially a corresponding neoplastic disease. The compounds offormula I or N-oxides thereof can be administered as such or especiallyin the form of pharmaceutical compositions, prophylactically ortherapeutically, preferably in an amount effective against the saiddiseases, to a warm-blooded animal, for example a human, requiring suchtreatment. In the case of an individual having a bodyweight of about 70kg the daily dose administered is from approximately 0.05 g toapproximately 5 g, preferably from approximately 0.25 g to approximately1.5 g, of a compound of the present invention.

The present invention relates especially also to the use of a compoundof formula I or N-oxides thereof, or a pharmaceutically acceptable saltthereof, especially a compound of formula I which is said to bepreferred, or a pharmaceutically acceptable salt thereof, as such or inthe form of a pharmaceutical formulation with at least onepharmaceutically acceptable carrier for the therapeutic and alsoprophylactic management of one or more of the diseases mentionedhereinabove, preferably a disease which responds to an inhibition of aprotein kinase, especially a neoplastic disease, more especiallyleukaemia which responds to an inhibition of the Abl tyrosine kinase.

The preferred dose quantity, composition, and preparation ofpharmaceutical formulations (medicines) which are to be used in eachcase are described above.

Starting Materials

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inthe preferred embodiment, such starting materials are used and reactionconditions so selected as to enable the preferred compounds to beobtained.

The substituted aminobenzoic acid of formula II, for example, can beobtained by reaction of an ester of 3-amino-4-R₄-benzoic acid, e.g.3-amino-4-methylbenzoic acid, with cyanamide and condensing theobtainable guanidine with3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one, and finally hyrolysingthe ester function.

Starting materials of the formula III are known, commercially available,or can be synthesized in analogy to or according to methods that areknown in the art.

The following Examples serve to illustrate the invention withoutlimiting the invention in its scope.

Abbreviations

DMSO dimethylsulfoxide

HPLC/MS-MS high-pressure liquid chromatography/tandem mass spectrometry

min minutes

m.p. melting point

NMP N-methyl-pyrrolidone

NMR nuclear magnetic resonance

PEG polyethylen glycol

THF tetrahydrofuran

EXAMPLES Example 1N-(2-Furanylmethyl)-4-methyl-3-[[4(3-pyridinyl)-2-pyrimidinyl]amino]benzamide

A solution containing ˜50% of propylphosphonic anhydride inN,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) isadded within 20 minutes to a stirred mixture of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4mg, 0.7 mmol), furfurylamine (Aldrich, Buchs, Switzerland; 61.8 μL, 0.7mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mLN,N-dimethylformamide. After stirring for 24 hours at room temperature,the mixture is treated with a half-saturated aqueous solution of sodiumhydrogen carbonate and extracted three times with ethyl acetate. Thesolvent is evaporated off under reduced pressure and the residue driedin vacuo. The crude product is crystallised from dichloromethane to givethe title compound as a crystalline solid.

¹H-NMR (400 MHz, DMSO-d₆, δ): 2.28 (s, 3H); 4.43 (d, 2H); 6.23 (m, 1H);6.33-6.37 (m, 1H); 7.30 (d,1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.53 (m,1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd,1H); 8.87 (t, 1H); 9.05 (s, 1H); 9.22 (m, 1H).

The starting material is prepared as follows:

Example 1a 3-[(Aminoiminomethyl)amino]-4-methyl-benzoic acid ethyl estermononitrate

Cyanamide-(Fluka, Buchs, Switzerland; 77.4 g, 1.842 mol) is added to asolution of 3-amino-4-methylbenzoic acid ethyl ester (J. Med. Chem.16,118-122,1973; 150 g, 0.837 mol) in 850 mL of ethanol. Hydrochloricacid (Fluka, Buchs, Switzerland; 108 mL of 12M, 1.27 mol) is then addeddropwise over 15 min and the reaction mixture is then stirred at 90° C.(bath temperature) for 15 hours. The solvent is evaporated off underreduced pressure to give a residue which is treated with water (1000 mL)and stirred with cooling at 5-10° C. A solution of ammonium nitrate(Merck, Darmstadt, Germany; 134.8 g, 1.68 mol) in water (400 mL) isadded dropwise over 30 min. followed by ice-water (1200 mL). Afterstirring for an additional 30 min. the product is filtered off, washedwith ice-water (3×1000 mL) and air-dried. The residue is washed withdiethyl ether (2×2000 m L) and dried in vacuo at 500 to give the titlecompound as a crystalline solid, m.p. 195-197° C.

Example 1b 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoicacid ethyl ester

A stirred mixture of the intermediate Example 1a (164 g, 0.577 mol),3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one (113.8 g, 0.646 mol)and powdered NaOH (99%; Merck, Darmstadt, Germany; 26.6 g, 0.658 mol) inethanol (2200 mL) is heated under reflux for 68 h. The reaction solventis evaporated off under reduced pressure and the residue partitionedbetween ethyl acetate and water. The organic layer is separated and theaqueous phase extracted twice with ethyl acetate. The combined organicextracts are washed with water and brine, dried (Na₂SO₄) and the solventis evaporated off under reduced pressure to give a residue, which iscrystallised from diethyl ether to give the title compound as acrystalline solid, m.p. 95-96° C.

Example 1c 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoicacid

Aqueous sodium hydroxide (500 mL of 2M) is added dropwise to a stirredsuspension of the intermediate Example 1b (132.8 g, 0.397 mol) inethanol (1200 mL) and water (1200 mL). The reaction mixture is stirredat 45° C. for 2.5 h and then treated dropwise with aqueous HCl (1000 mLof 1 M) over 1.5 hours. After addition of water (1000 mL) theprecipitate is filtered off, washed with water (4×500 mL) and dried atroom temperature. Residual water present in the air-dried product isremoved by azeotropic distillation with toluene under reduced pressure.The dried toluene suspension is diluted with diethyl ether and filtered.The solid residue is washed with diethyl ether and dried in vacuo at 80°C. to give the title compound, m.p. 277-278° C.

Example 2N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-[(4-methyl-1-piperazinyl)methyl]benzeneamine

A solution containing ˜50% of propylphosphonic anhydride inN,N-dimethylformamide (Fluka, Buchs, Switzerland; 875 μL, ˜1.5 mmol) isadded within 20 minutes to a stirred mixture of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg,1.0 mmol), 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine (Chem. Abstr.Reg. Number: 70261-82-4; 205 mg, 1.0 mmol) and triethylamine (83 μL, 6.0mmol) in 8 mL N,N-dimethylformamide. After stirring for 24 hours at roomtemperature, the mixture is treated with a saturated aqueous ammoniumchloride and extracted three times with ethyl acetate. The solvent isevaporated off under reduced pressure and the residue dried in vacuo.The crude product is crystallised from ethanol-ethyl acetate to give thetitle compound as a crystalline solid, m.p. 153-155° C.

Example 31-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(2-pyridinyl)-piperazine

A solution containing ˜50% of propylphosphonic anhydride inN,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) isadded within 20 minutes to a stirred mixture of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4mg, 0.7 mmol), 1-(2-pyridyl)piperazine (Aldrich, Buchs, Switzerland;114.3 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mLN,N-dimethylformamide. After stirring for 24 hours at room temperature,the mixture is treated with a half-saturated aqueous solution of sodiumhydrogen carbonate and extracted three times with ethyl acetate. Thesolvent is evaporated off under reduced pressure and the residue driedin vacuo. The crude product is purified by column chromatography onsilica gel, eluent 5-10% methanol in dichloromethane, to give the titlecompound as a solid. ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.31 (s, 3H);3.35-3.74 (m, 8H); 6.65 (ddd, 1H); 6.79 (d, 1H); 7.13 (dd, 1H); 7.32 (d,1H); 7.44 (d, 1H); 7.49-7.56 (m, 2H); 7.69 (m, 1H); 8.11 (m, 1H); 8.40(m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).

The following compounds are prepared analogously by utilising theappropriate amine (supplier in parenthesis):

Example 4

4-Methyl-N-[2-(2-pyridinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 2-(2-aminoethyl)pyridine (Fluka, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 2.27 (s, 3H); 2.97 (t, 2H); 3.58 (m, 2H); 7.18(ddd, 1H); 7.25 (m, 1H); 7.29 (d,1H); 7.42 (d, 1H); 7.47-7.56 (m, 2H);7.65 (m, 1H); 8.06 (d, 1H); 8.39 (m, 1H); 8.44-8.51 (m, 3H); 8.66 (dd,1H); 9.04 (s, 1H); 9.22 (m, 1H).

Example 5

4-Methyl-N-[1-(phenylmethyl)-4-piperidinyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising 4-amino-1-benzylpiperidine (Aldrich, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 1.47-1.63 (m, 2H); 1.69-1.80 (m, 2H);1.92-2.05 (m, 2H); 2.27 (s, 3H); 2.73-2.83 (m, 2H); 3.43 (s, 2H);3.68-3.83 (m, 1H); 7.18-7.33 (m,6H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.55(dd, 1H); 8.10 (m, 1H); 8.14 (d, 1H); 8.37 (m, 1H); 8.49 (d, 1H); 8.65(dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).

Example 6

4-Methyl-N-(4-pyridinylmethyl)-3-[[4-(3-pyridinyl)-2-pyrimidiny]amino]benzamideutilising 4-(aminomethyl)pyridine (Aldrich, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 2.30 (s, 3H); 4.46 (d, 2H); 7.26 (m, 2H); 7.33(d, 1H); 7.43 (d, 1H); 7.47 (ddd, 1H); 7.62 (dd, 1H); 8.16 (d, 1H); 8.38(m, 1H); 8.45 (m, 2H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.03 (t, 1H); 9.08(s, 1H); 9.23 (m, 1H).

Example 7

4-Methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising 2-(2-aminoethyl)-1-methylpyrrol [Chem. Abstr. Reg. Number:83732-75-6]. ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.28 (s, 3H); 2.75 (t, 2H);3.42 (m, 2H); 3.51 (s, 3H); 5.76-5.85 (m, 2H); 6.57 (m,1H); 7.30 (d,1H);7.43 (d, 1H); 7.46-7.58 (m, 2H); 8.10 (br. 1H); 8.40 (m, 1H); 8.48-8.55(m, 2H); 8.64-8.69 (m, 1H); 9.05 (s, 1H); 9.23 (m, 1H).

Example 8

N-[(4-Methoxyphenyl)methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 4-methoxybenzylamine (Fluka, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 2.28 (s, 3H); 3.69 (s, 3H); 4.37 (d, 2H); 6.80-6.87(m, 2H); 7.17-7.23 (m, 2H); 7.31 (d,1H); 7.42 (d, 1H); 7.47 (ddd, 1H);7.59 (dd, 1H); 8.11 (d, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H);8.87 (t, 1H); 9.05 (s, 1H); 9.23 (m, 1H).

Example 9

4-Methyl-N-(2-methylpropyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising isobutylamine (Fluka, Buchs, Switzerland). ¹H-NMR (400 MHz,DMSO-d₆, δ): 0.85 (d, 6H); 1.81 (m, 1H); 2.27 (s, 3H); 3.04 (m, 2H);7.29 (d,1H); 7.42 (d, 1H); 7.48 (dd, 1H); 7.55 (dd, 1H); 8.07 (d, 1H);8.31-8.41 (m, 2H); 8.49 (d, 1H); 8.65 (dd, 1H); 9.05 (s, 1H); 9.22 (m,1H).

Example 10

4-Methyl-N-(2-morpholinoethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 4-(2-aminoethyl)morpholine (Fluka, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 2.28 (s, 3H); 2.33-2.46 (m, 6H); 3.30-3.40 (m,2H); 3.53 (m, 4H); 7.30 (d,1H); 7.42 (d, 1H); 7.46-7.57 (m, 2H); 8.06(d, 1H); 8.30 (m, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.05(s, 1H); 9.22 (m, 1H).

Example 11

4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(tetrahydro-2-furanyl)-methyl]benzamideutilising tetrahydrofurfurylamine (Fluka, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 1.49-1.63 (m, 1H); 1.70-1.93 (m, 3H); 2.27 (s,3H); 3.27 (m, 2H); 3.58 (m, 1H); 3.72 (m, 1H); 3.94 (m, 1H); 7.29(d,1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.56 (dd, 1H); 8.08 (d, 1H);8.35-8.45 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.21 (m,1H).

Example 12

N-[2-(2,4-Dihydroxy-5-pyrimidinyl)ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising 5-(2-aminoethyl)-2,4(1H,3H)-pyrimidinedione [Chem. Abstr. Reg.Number: 221170-25-8]. ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.27 (s, 3H); 2.40(t, 2H); 3.34 (m, 2H); 7.15 (m,1H); 7.29 (d,1H); 7.42 (d, 1H); 7.47-7.55(m, 2H); 8.07 (d, 1H); 8.35-8.42 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H);9.04 (s, 1H); 9.22 (m, 1H); 10.59 (s, 1H); 11.01 (s, 1H).

Example 13

N-Cyclohexyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising cyclohexylamine (Fluka, Buchs, Switzerland). ¹H-NMR (400 MHz,DMSO-d₆, δ): 1.00-1.16 (m, 1H); 1.18-1.36 (m, 4H); 1.52-1.85 (m, 5H);2.27 (s, 3H); 3.663.82 (m, 1H); 7.28 (d, 1H); 7.41 (d, 1H); 7.48 (m,1H); 7.55 (dd, 1H); 8.06-8.12 (m, 2H); 8.37 (m, 1H); 8.49 (d, 1H); 8.66(dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).

Example 14

N-[(3S)-Hexahydro-2-oxo-1H-azepin-3-yl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising L(−)-alpha-amino-epsilon-caprolactam [Chem. Abstr. Reg.Number: 21568-87-6]. ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.11-1.31 (m, 1H);1.37-1.82 (m, 3H); 1.83-1.96 (m, 2H); 2.28 (s, 3H); 3.00-3.13 (m, 1H);3.15-3.30 (m, 1H); 4.58 (m, 1H); 7.32 (d,1H); 7.43 (d, 1H); 7.51 (ddd,1H); 7.55 (dd, 1H); 7.84 (m, 1H); 8.08 (d, 1H); 8.13 (d, 1H); 8.40 (m,1H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.22 (m, 1H).

Example 15

N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising 2-(3,4-dimethoxyphenyl)ethylamine (Fluka, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 2.27 (s, 3H); 2.75 (t, 2H); 3.43 (m, 2H);3.67 (s, 6H); 6.70 (dd, 1H); 6.77-6.83 (m, 2H); 7.30 (d,1H); 7.42 (d,1H); 7.46-7.57 (m, 2H); 8.07 (d, 1H); 8.36-8.46 (m, 2H); 8.49 (d, 1H);8.66 (dd, 1H); 9.05 (s, 1H); 9.22 (m, 1H).

Example 16

2-[[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]-4-thiazole-aceticacid ethyl ester utilising ethyl 2-amino-4-thiazoleacetate (Aldrich,Buchs, Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.16 (t, 3H); 2.32(s, 3H); 3.70 (s, 2H); 4.06 (q, 2H); 7.01 (s, 1H); 7.36 (d,1H);7.42-7.54 (m, 2H); 7.82 (d, 1H); 8.34-8.47 (m, 2H); 8.52 (d, 1H); 8.66(m, 1H); 9.08 (s, 1H); 9.24 (m, 1H); 12.57 (br., 1H).

Example 17

N-[3-(1H-Imidazol-1-yl)propyl]-4-methyl-3-[[4-(3-pyridinyl)-2pyrimidinyl]amino]-benzamideutilising 1-(3-aminopropyl)imidazole (Aldrich, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 1.96 (qui, 2H); 2.30 (s, 3H); 3.24 (m,2H); 4.01 (t, 2H); 6.91 (s,1H); 7.22 (m, 1H); 7.34 (d,1H); 7.45 (d, 1H);7.51 (ddd, 1H); 7.59 (dd, 1H); 7.70 (s, 1H); 8.14 (d, 1H); 8.42 (m, 1H);8.47 (t, 1H); 8.52 (d, 1H); 8.68 (dd, 1H); 9.10 (s, 1H); 9.25 (m, 1H).

Example 18

N-(Cyclopropylmethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising cyclopropanemethylamine (Fluka, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 0.17-0.22 (m, 2H); 0.36-0.42 (m, 2H); 0.96-1.06(m, 1H); 2.28 (s, 3H); 3.11 (m, 2H); 7.31 (d,1H); 7.43 (d, 1H); 7.50(ddd, 1H); 7.58 (dd, 1H); 8.10 (d, 1H); 8.40 (m, 1H); 8.47 (t, 1H); 8.50(d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).

Example 19

N-(2-methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising 2-methoxyethylamine (Fluka, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 2.28 (s, 3H); 3.23 (s, 3H); 3.36-3.46 (m, 4H); 7.31(d,1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.57 (dd, 1H); 8.10 (d, 1H);8.38-8.47 (m, 2H); 8.50 (d, 1H); 8.68 (dd, 1H); 9.07 (s, 1H); 9.23 (m,1H).

Example 20

4-Methyl-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising 1-(3-aminopropyl)-2-pyrrolidinone (Aldrich, Buchs,Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.67 (m, 2H); 1.89 (m, 2H);2.18 (t, 2H); 2.28 (s, 3H); 3.19 (m, 4H); 3.32 (m, 2H); 7.30 (d, 1H);7.42 (d, 1H); 7.49 (ddd, 1H); 7.54 (dd, 1H); 8.09 (d, 1H); 8.31-8.42 (m,2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).

Example 21

N,4-Dimethyl-N-(phenylmethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising N-benzylmethylamine (Fluka, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 2.28 (s, 3H); 2.86 (s, 3H); 4.51-4.68 (m, 2H);7.08-7.35 (m,7H); 7.43 (d, 1H); 7.48 (m, 1H); 7.71 (s, 1H); 8.35-8.54(m, 2H); 8.67 (m, 1H); 8.97-9.09 (m, 1H); 9.24 (m, 1H).

Example 22

N-[4-(Acetylamino)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 4-aminoacetanilide (Fluka, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 2.01 (s, 3H); 2.32 (s, 3H); 7.38 (d,1H); 7.45 (d, 1H);7.47-7.54 (m, 3H); 7.63-7.71 (m, 3H); 8.22 (m, 1H); 8.43 (m, 1H); 8.52(d, 1H); 8.67 (dd, 1H); 9.13 (s, 1H); 9.25 (m, 1H); 9.90 (s, 1H); 10.11(s, 1H).

Example 23

N-(4-Methoxy-2-methylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 4-methoxy-2-methylaniline (Aldrich, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 2.16 (s, 3H); 2.32 (s, 3H); 3.73 (s, 3H);6.75 (dd, 1H); 6.82 (m, 1H); 7.16 (d, 1H); 7.37 (d,1H); 7.45 (d, 1H);7.49 (ddd, 1H); 7.69 (dd, 1H); 8.25 (d, 1H); 8.41 (m, 1H); 8.52 (d, 1H);8.67 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 9.69 (s, 1H).

Example 24

4-Methyl-N-[4-(methylsulfonyl)benzyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 4-methylsulfonylbenzylamine hydrochloride (Acros, MorrisPlains, N.J.). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.30 (s, 3H); 3.16 (s, 3H);4.54 (d, 2H); 7.34 (d,1H); 7.44 (d, 1H); 7.49 (ddd, 1H); 7.55 (m, 2H);7.63 (dd, 1H); 7.86 (m, 2H); 8.16 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H);8.67 (dd, 1H); 9.10 (m, 2H); 9.24 (m, 1H).

Example 25

N-[[4-(Dimethylamino)phenyl]methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising 4-(dimethylamino)benzylamine dihydrochloride (Aldrich, Buchs,Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.28 (s, 3H); 2.82 (s, 6H);4.32 (d, 2H); 6.64 (m, 2H); 7.11 (m, 2H); 7.31 (d, 1H); 7.43 (d, 1H);7.48 (ddd, 1H); 7.59 (dd, 1H); 8.12 (d, 1H); 8.39 (m, 1H); 8.50 (d, 1H);8.68 (dd, 1H); 8.81 (t, 1H); 9.07 (s, 1H); 9.24 (m, 1H).

Example 26

N-(2-Amino-2-oxoethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising glycinamide hydrochloride (Fluka, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 2.29 (s, 3H); 3.78 (d, 2H); 7.02 (s, 1H);7.30-7.36 (m, 2H); 7.44 (d, 1H); 7.53 (ddd, 1H); 7.61 (dd, 1H); 8.11 (m,1H); 8.41 (m, 1H); 8.50 (d, 1H); 8.57 (t, 1H); 8.67 (dd, 1H); 9.08 (s,1H); 9.24 (m, 1H).

Example 27

N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]glycinemethyl ester utilising glycine methylester hydrochloride (Fluka, Buchs,Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.29 (s, 3H); 3.63 (s, 3H);3.98 (d, 2H); 7.34 (d,1H); 7.44 (d, 1H); 7.52 (ddd, 1H); 7.59 (dd, 1H);8.11 (d, 1H); 8.41 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 8.87 (t, 1H);9.09 (s, 1H); 9.23 (m, 1H).

Example 28

N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]beta-alaninemethyl ester utilising beta-alanine methylester hydrochloride (Fluka,Buchs, Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.27 (s, 3H); 2.57(t, 2H); 3.46 (m, 2H); 3.57 (s, 3H); 7.31 (d, 1H); 7.43 (d, 1H);7.50-7.55 (m, 2H); 8.07 (d, 1H); 8.40 (m, 1H); 8.47 (t, 1H); 8.50 (d,1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).

Example 29

N-[[4-(Aminosulfonyl)phenyl]methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising p-(aminomethyl)benzenesulfonamide hydrochloride (Sigma, Buchs,Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.29 (s, 3H); 4.51 (d, 2H);7.30 (s, 2H); 7.34 (d, 1H); 7.43-7.50 (m, 4H); 7.62 (dd, 1H); 7.75 (m,2H); 8.16 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.06 (t,1H); 9.09 (s, 1H); 9.24 (m, 1H).

Example 30

N-(3-Hydroxypropyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising 3-amino-1-propanol (Aldrich, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 1.65 (qui, 2H); 2.28 (s, 3H); 3.29 (m, 2H); 3.42 (m,2H); 4.50 (m, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.56 (dd,1H); 8.09 (d, 1H); 8.36-8.43 (m, 2H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07(s, 1H); 9.23 (m, 1H).

Example 31

N,N-Diethyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising diethylamine (Fluka, Buchs, Switzerland). ¹H-NMR (400 MHz,DMSO-d₆, δ): 1.04 (m, 6H); 2.28 (s, 3H); 3.31 (m, 4H); 7.02 (dd, 1H);7.27 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.61 (m, 1H); 8.39 (m, 1H);8.51 (d, 1H); 8.68 (dd, 1H); 9.01 (s, 1H); 9.23 (m, 1H).

Example 32

N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-(L)-phenylalanine1,1-dimethylethyl ester utilising L-phenylalanine t-butylesterhydrochloride (Novabiochem (Juro), Lucerne, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 1.32 (s, 9H); 2.28 (s, 3H); 3.07 (m, 2H); 4.53 (m,1H); 7.13-7.29 (m, 5H); 7.32 (d, 1H); 7.44 (d, 1H); 7.50 (ddd, 1H); 7.55(dd, 1H); 8.05 (m, 1H); 8.39 (m, 1H); 8.49 (d, 1H); 8.63 (d, 1H); 8.67(dd, 1H); 9.08 (s, 1H); 9.23 (m, 1H).

Example 33

N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-(D)-alanine1,1-dimethylethyl ester utilising D-alanine t-butylester hydrochloride(Novabiochem (Juro), Lucerne, Switzerland). ¹H-NMR (400 MHz, DMSO-d₆,δ): 1.34 (d, 3H); 1.38 (s, 9H); 2.28 (s, 3H); 4.32 (m, 1H); 7.33 (d,1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.61 (dd, 1H); 8.14 (m, 1H); 8.40 (m,1H); 8.50 (m, 1H); 8.58 (d, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.23 (m,1H).

Example 34

N-[1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-piperidinyl]-benzamideutilising N-4-piperidinyl-benzamide (Maybridge Chemical Co. Ltd). ¹H-NMR(400 MHz, DMSO-d₆, δ): 1.49 (m, 2H); 1.68-1.94 (m, 2H); 2.30 (s, 3H);2.92 (m, 1H); 3.16 (m, 1H); 3.79 (m, 1H); 4.05 (m, 1H); 4.42 (m, 1H);7.08 (dd, 1H); 7.31 (d, 1H); 7.41-7.54 (m, 5H); 7.63 (m, 1H); 7.79-7.84(m, 2H); 8.28 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.06(s, 1H); 9.24 (m, 1H).

Example 35

4-[4-Methyl-3-[[4(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-morpholineutilising morpholine (Fluka, Buchs, Switzerland). ¹H-NMR (400 MHz,DMSO-d₆, δ): 2.29 (s, 3H); 3.47 (m, 8H); 7.10 (dd, 1H); 7.30 (d, 1H);7.44 (m, 1H); 7.52 (ddd, 1H); 7.65 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H);8.69 (dd, 1H); 9.05 (s, 1H); 9.23 (m, 1H).

Example 36

1-(4-Methoxyphenyl)-4-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoyl]piperazineutilising 1-(4-methoxyphenyl)-piperazine (Emka Chemie, Neufahrn,Germany). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.30 (s, 3H); 2.87-3.08 (m, 4H);3.50-3.75 (m, 4H); 3.67 (s, 3H); 6.78-6.88 (m, 4H); 7.12 (dd, 1H); 7.31(d, 1H); 7.44 (m, 1H); 7.51 (ddd, 1H); 7.67 (m, 1H); 8.38 (m, 1H); 8.52(m, 1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 37

1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(4-pyridinyl)-piperazineutilising 1-(4-pyridyl)-piperazine (Emka Chemie, Neufahrn, Germany).¹H-NMR (400 MHz, DMSO-d₆, δ): 2.31 (s, 3H); 3.30 (m, 4H); 3.59 (m, 4H);6.77 (m, 2H); 7.14 (dd, 1H); 7.32 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H);7.70 (m, 1H); 8.16 (m, 2H); 8.41 (m, 1H); 8.53 (d, 1H); 8.67 (dd, 1H);9.07 (s, 1H); 9.24 (m, 1H).

Example 38

1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(pyrazinyl)-piperazineutilising 1-(2-pyrazinyl)-piperazine (Emka Chemie, Neufahrn, Germany).¹H-NMR (400 MHz, DMSO-d₆, δ): 2.31 (s, 3H); 3.57 (m, 8H); 7.14 (dd, 1H);7.32 (d, 1H); 7.45 (d, 1H); 7.51 (ddd, 1H); 7.72 (m, 1H); 7.85 (d, 1H);8.08 (d, 1H); 8.29 (d, 1H); 8.40 (m, 1H); 8.53 (d, 1H); 8.65 (dd, 1H);9.06 (s, 1H); 9.24 (m, 1H).

Example 39

1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(phenylmethyl)-piperazineutilising 1-benzyl-piperazine (Aldrich, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 2.21-2.42 (m, 4H); 2.28 (s, 3H); 3.34-3.63 (m, 6H);7.07 (dd, 1H); 7.21-7.34 (m, 6H); 7.43-7.50 (m, 2H); 7.63 (m, 1H); 8.38(m, 1H); 8.50 (d, 1H); 8.65 (dd, 1H); 9.03 (s, 1H); 9.22 (m, 1H).

Example 40

1-Cyclopentyl-4-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-piperazineutilising 1-cyclopentyl-piperazine (Emka Chemie, Neufahrn, Germany).¹H-NMR (400 MHz, DMSO-d₆, δ): 1.20-1.31 (m, 2H); 1.39-1.62 (m, 4H);1.65-1.75 (m, 2H); 2.18-2.47 (m, 8H); 3.27-3.62 (m, 4H); 7.08 (dd, 1H);7.29 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.62 (m, 1H); 8.38 (m, 1H);8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).

Example 41

4-{{4-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1-piperazinyl}-acetyl}morpholineutilising 4-[2-(piperazin-1-yl)-acetyl]-morpholine (Emka Chemie,Neufahrn, Germany). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.29 (s, 3H);2.31-2.49 (m, 4H); 3.16 (s, 2H); 3.37-3.60 (m, 12H); 7.07 (dd, 1H); 7.29(d,1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.65 (m, 1H); 8.39 (m, 1H); 8.51(d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.23 (m, 1H).

Example 42

1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-[2-oxo-2-(1-pyrrolidinyl)ethyl]piperazineutilising 1-[2-(piperazin-1-yl)-acetyl-pyrrolidine (Emka Chemie,Neufahrn, Germany). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.73 (m, 2H); 1.83 (m,2H); 2.29 (s, 3H); 2.43 (m, 4H); 3.09 (s, 2H); 3.25 (m, 2H); 3.34-3.63(m, 6H); 7.07 (dd, 1H); 7.29 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.64(m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.22(m, 1H).

Example 43

4-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1-piperazine-carboxylicacid ethyl ester utilising ethyl 1-piperazinecarboxylate (Aldrich,Buchs, Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.16 (t, 3H); 2.29(s, 3H); 3.19-3.63 (m, 8H); 4.02 (q, 2H); 7.10 (dd, 1H); 7.30 (d, 1H);7.45 (d, 1H); 7.52 (ddd, 1H); 7.66 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H);8.68 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 44

2-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1,2,3,4-tetrahydro-isoquinolineutilising 1,2,3,4-tetrahydroisoquinoline (Fluka, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 2.31 (s, 3H); 2.79 (m, 2H); 3.57-3.90 (m,2H); 4.58-4.79 (m, 2H); 7.08-7.23 (m, 5H); 7.32 (d, 1H); 7.42-7.50 (m,2H); 7.70 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.05 (s,1H); 9.24 (m, 1H).

Example 45

N,N-bis(2-Methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidiny]amino]-benzamideutilising bis(2-methoxyethyl)amine (Aldrich, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 2.28 (s, 3H); 3.09 (br.s, 3H); 3.23 (br.s, 3H);3.47 (m, 8H); 7.04 (dd, 1H); 7.27 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H);7.62 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.01 (s, 1H);9.23 (m, 1H).

Example 46

1′-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1,4′-bipiperidineutilising 4-piperidinopiperidine (Aldrich, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 1.21-1.50 (m, 8H); 1.51-1.83 (m, 2H); 2.29 (s,3H); 2.39 (m, 4H); 2.68 (m, 1H); 2.95 (m, 1H); 3.71 (m, 1H); 4.42 (m,1H); 7.07 (dd, 1H); 7.28 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.63 (m,1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.03 (s, 1H); 9.23 (m,1H).

Example 47

N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-N-(phenylmethyl)-glycineethyl ester utilising N-benzylglycine ethyl ester (Fluka, Buchs,Switzerland). ¹H-NMR (300 MHz, DMSO-d₆, δ): 0.97-1.20 (m, 3H); 2.27 (s,3H); 3.90-4.12 (m, 4H); 4.58-4.68 (m, 2H); 7.07 (m, 1H); 7.15-7.34 (m,6H); 7.38-7.53 (m, 2H); 7.65-7.74 (m, 1H); 8.35-8.51 (m, 2H); 8.66 (dd,1H); 8.96-9.04 (m, 1H); 9.22 (m, 1H).

Example 48

N-(3-Chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising 3-chlor-aniline (Fluka, Buchs, Switzerland). ¹H-NMR (400 MHz,DMSO-d₆, δ): 2.33 (s, 3H); 7.14 (m, 1H); 7.36 (m, 1H); 7.41 (d, 1H);7.46 (d, 1H); 7.49 (ddd, 1H); 7.68-7.73 (m, 2H); 7.95 (m, 1H); 8.25 (m,1H); 8.43 (m, 1H); 8.53 (d, 1H); 8.66 (dd, 1H); 9.15 (s, 1H); 9.26 (m,1H); 10.33 (s, 1H).

Example 49

N-(2,2-Diphenylethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 2,2-diphenylethylamine (Aldrich, Buchs, Switzerland). ¹H-NMR(400 MHz, DMSO-d₆, δ): 2.24 (s, 3H); 3.87 (m, 2H); 4.41 (m, 1H);7.12-7.17 (m, 2H); 7.23-7.31 (m, 9H); 7.41-7.44 (m, 2H); 7.51 (ddd, 1H);7.97 (m, 1H); 8.37-8.44 (m, 2H); 8.48 (d, 1H); 8.68 (dd, 1H); 9.05 (s,1H); 9.23 (m, 1H).

Example 50

N-(2,3-Dihydro-1H-inden-1-yl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 1-Aminoindane (Fluka, Buchs, Switzerland). ¹H-NMR (400 MHz,DMSO-d₆, δ): 1.90-2.01 (m, 1H); 2.29 (s, 3H); 2.43 (m, 1H); 2.77-2.86(m, 1H); 2.91-2.98 (m, 1H); 5,56 (m, 1H); 7.08-7.25 (m, 4H); 7.31 (d,1H); 7.43 (d, 1H); 7.50 (ddd, 1H); 7.64 (dd, 1H); 8.20 (m, 1H); 8.40 (m,1H); 8.50 (d, 1H); 8.68-8.72 (m, 2H); 9.08 (s, 1H); 9.24 (m, 1H).

Example 51

N-(Diphenylmethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising alpha-aminodiphenylmethane (Fluka, Buchs, Switzerland) ¹H-NMR(400 MHz, DMSO-d₆, δ): 2.29 (s, 3H); 6.41 (d, 1H); 7.20-7.36 (m, 11H);7.43 (d, 1H); 7.46 (ddd, 1H); 7.67 (dd, 1H); 8.18 (m, 1H); 8.38 (m, 1H);8.50 (d, 1H); 8.68 (dd, 1H); 9.10 (s, 1H); 9.20 (d, 1H); 9.24 (m, 1H).

Example 52

4-Methyl-N-[2-(1-piperidinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 1-(2-aminoethyl)piperidine (Aldrich, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 1.30-1.38 (m, 2H); 1.41-1.48 (m, 4H); 2.28(s, 3H); 2.31-2.41 (m, 6H); 3.33 (m, 2H); 7.31 (d, 1H); 7.44 (d, 1H);7.51 (ddd, 1H); 7.55 (dd, 1H); 8.08 (m, 1H); 8.28 (t, 1H); 8.40 (m, 1H);8.51 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24 (m, 1H).

Example 53

4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(5,6,7,8-tetrahydro-1-naphthalenyl)benzamideutilising 5,6,7,8-tetrahydro-1-naphthylamine (Aldrich, Buchs,Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.63-1.71 (m, 4H); 2.32 (s,3H); 2.60 (m, 2H); 2.74 (m, 2H); 6.96 dd, 1H); 7.07-7.14 (m, 2H); 7.37(d, 1H); 7.45 (d, 1H); 7.49 (ddd, 1H); 7.69 (dd, 1H); 8.25 (m, 1H); 8.41(m, 1H); 8.52 (d, 1H); 8.67 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 9.65(br.s).

Example 54

4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[[4-(trifluoromethyl)phenyl]-methyl]benzamideutilising 4-(trifluoromethyl)benzylamine (Aldrich, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 2.30 (s, 3H); 4.53 (d, 2H); 7.34 (d,1H);7.44 (d, 1H); 7.46-7.53 (m, 3H); 7.62 (dd, 1H); 7.66 (m, 2H); 8.16 (m,1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.08 (t, 1H); 9.10 (s,1H); 9.24 (m, 1H).

Example 55

4-Methyl-N-[(5-methylpyrazinyl)methyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 2-(aminomethyl)-5-methylpyrazine (TCI-JP, Distrib. Zürich,Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.29 (s, 3H); 2.45 (s, 3H);4.54 (d, 2H); 7.33 (d, 1H); 7.44 (d, 1H); 7.49 (ddd, 1H); 7.62 (dd, 1H);8.14 (m, 1H); 8.40 (m, 1H); 8.45 (m, 2H); 8.50 (d, 1H); 8.66 (dd, 1H);9.07 (t, 1H); 9.09 (s, 1H); 9.23 (m, 1H).

Example 56

N-(2-Ethoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising 2-ethoxyethylamine (TCI-JP, Distrib. Zurich, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ):1.07 (t, 3H); 2.28 (s, 3H); 3.30-3.49 (m,6H); 7.31 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.57 (dd, 1H); 8.09 (m,1H); 8.38-8.45 (m, 2H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24(m, 1H).

Example 57

4-Methyl-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising 1-(2-aminoethyl)imidazolidin-2-one [Chem. Abstr. Reg. Number:6281-42-1]. ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.27 (s, 3H); 3.13-3.22 (m,4H); 3.30-3.40 (m, 4H); 6.27 (br.s, 1H); 7.30 (d, 1H); 7.43 (d, 1H);7.49-7.56 (m, 2H); 8.08 (d, 1H); 8.40 (m, 1H); 8.45 (t, 1H); 8.50 (d,1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 58

4-Methyl-N-(5-methyl-2-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamideutilising 2-amino-5-picoline (Aldrich, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 2.26 (s, 3H); 2.32 (s, 3H); 7.35 (d, 1H); 7.45 (d,1H); 7.49 (ddd, 1H); 7.64 (dd, 1H); 7.77 (dd, 1H); 8.07 (d, 1H); 8.18(m, 1H); 8.31 (d, 1H); 8.43 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.08(s, 1H); 9.25 (m, 1H); 10.58 (s, 1H).

Example 59

1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-phenyl-4-piperidinolutilising 4-hydroxy-4-phenylpiperidine (Aldrich, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 1.45-1.73 (m, 2H); 1.88 (m, 2H); 2.28 (s,3H); 3.15 (m, 1H); 3.47 (m, 1H); 3.64 (m, 1H); 4.39 (m, 1H); 5.14 (s,1H); 7.14 (dd, 1H); 7.19 (m, 1H); 7.26-7.31 (m, 3H); 7.43 (d, 1H);7.45-7.51 (m, 3H); 7.69 (d, 1H); 8.40 (m, 1H); 8.48 (d, 1H); 8.67 (dd,1H); 9.03 (s, 1H); 9.24 (m, 1H).

Example 60

N-(3-Benzoylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamideutilising 3-aminobenzophenone (Aldrich, Buchs, Switzerland). ¹H-NMR (400MHz, DMSO-d₆, δ): 2.32 (s, 3H); 7.39 (d, 1H); 7.43-7.58 (m, 6H); 7.67(m, 1H); 7.70-7.77 (m, 3H); 8.13 (m, 1H); 8.20 (m, 1H); 8.27 (m, 1H);8.42 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.14 (s, 1H); 9.25 (m, 1H);10.41 (s, 1H).

Example 61

N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-glycine1,1-dimethylethyl ester utilising glycine t-butyl ester hydrochloride(Aldrich, Buchs, Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.40 (s,9H); 2.29 (s, 3H); 3.86 (d, 2H); 7.33 (d, 1H); 7.43 (d, 1H); 7.51 (ddd,1H); 7.58 (dd, 1H); 8.10 (d, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.67 (dd,1H); 8.75 (t, 1H); 9.08 (s, 1H); 9.23 (m, 1H).

Example 62

4-[[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamino]benzene-aceticacid ethyl ester utilising ethyl 4-aminophenylacetate (MaybridgeChemical Co. Ltd.). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.16 (t, 3H); 2.32 (s,3H); 3.60 (s, 2H); 4.06 (q, 2H); 7.21 (m, 2H); 7.38 (d, 1H); 7.45 (d,1H); 7.48 (ddd, 1H); 7.70 (m, 3H); 8.23 (m, 1H); 8.41 (m, 1H); 8.52 (d,1H); 8.66 (dd, 1H); 9.13 (s, 1H); 9.25 (m, 1H); 10.16 (s, 1H).

Example 63

4-Methyl-N-[3-(methylphenylamino)propyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising N-(3-aminopropyl)-N-methylaniline (TCI-JP, Distrib. Zürich,Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.73 (qui, 2H); 2.28 (s,3H); 2.84 (s, 3H); 3.24-3.37 (m, 4H); 6.55 (m, 1H); 6.65 (m, 2H); 7.10(m, 2H); 7.31 (d, 1H); 7.43 (d, 1H); 7.47 (ddd, 1H); 7.55 (dd, 1H); 8.10(d, 1H); 8.37-8.44 (m, 2H); 8.50 (d, 1H); 8.65 (dd, 1H); 9.06 (s, 1H);9.23 (m, 1H).

Example 64

1-[[3-[[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]phenyl]-methyl]-4-piperidinecarboxylicacid ethyl ester utilising ethyl1-(3-aminobenzyl)piperidine-4-carboxylate (Maybridge Chemical Co. Ltd.).¹H-NMR (400 MHz, DMSO-d₆, δ): 1.14 (t, 3H); 1.49-1.61 (m, 2H); 1.72-1.80(m, 2H); 1.92-2.02 (m, 2H); 2.27 (m, 1H); 2.32 (s, 3H); 2.74 (m, 2H);3.40 (s, 2H); 4.03 (q, 2H); 6.98 (d, 1H); 7.25 (m, 1H); 7.38 (d, 1H);7.43-7.51 (m, 2H); 7.66-7.73 (m, 3H); 8.25 (s, 1H); 8.42 (m, 1H); 8.52(d, 1H); 8.65 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 10.14 (s, 1H).

Example 65

[[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]propanedioicacid diethyl ester utilising diethyl aminomalonate hydrochloride(Aldrich, Buchs, Switzerland). ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.19 (t,6H); 2.30 (s, 3H); 4.10-4.22 (m, 4H); 5.27 (d, 1H); 7.35 (d, 1H); 7.44(d, 1H); 7.51 (ddd, 1H); 7.63 (dd, 1H); 8.15 (m, 1H); 8.40 (m, 1H); 8.50(d, 1H); 8.67 (dd, 1H); 9.11 (s, 1H); 9.21-9.25 (m, 2H).

Example 66

N-[2-[bis(1-Methylethyl)amino]ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamideutilising 2-diisopropylamino-ethylamine (Fluka, Buchs, Switzerland).¹H-NMR (400 MHz, DMSO-d₆, δ): 0.95 (m, 12H); 2.28 (s, 3H); 2.49 (m, 2H);2.94 (m, 2H); 3.17 (m, 2H); 7.30 (d, 1H); 7.43 (d, 1H); 7.50 (ddd, 1H);7.54 (dd, 1H); 8.09 (br.s, 1H); 8.27 (m, 1H); 8.40 (m, 1H); 8.50 (d,1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).

Example 67

N-[3-(Diethylamino)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide

A solution containing ˜50% of propylphosphonic anhydride inN,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1.05 mmol) isadded within 20 minutes to a stirred mixture of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4mg, 0.7 mmol), N,N-diethyl-1,3-benzenediamine (115 mg, 0.7 mmol) andtriethylamine (776 μL , 5.6 mmol) in 2 mL N,N-dimethylformamide. Afterstirring for 24 hours at room temperature, the mixture is treated with ahalf-saturated aqueous solution of sodium hydrogen carbonate andextracted three times with ethyl acetate. The solvent is evaporated offunder reduced pressure and the residue dried in vacuo. The crude productis purified by chromatography on silica gel, eluent 2% methanol indichloromethane and crystallised from acetone to give the title compoundas a crystalline solid. ¹H-NMR (400 MHz, DMSO-d₆, δ): 1.07 (t, 6H); 2.31(s, 3H); 3.29 (m, 4H); 6.38 (m, 1H); 7.06 (m, 2H); 7.11 (m, 1H); 7.36(d, 1H); 7.43-7.50 (m, 2H); 7.67 (m, 1H); 8.21 (m, 1H); 8.43 (m, 1H);8.51 (d, 1H); 8.66 (dd, 1H); 9.12 (s, 1H); 9.24 (m, 1H); 9.90 (s, 1H).

Example 684-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[[3-[(1-hydroxy-1-methyl-ethyl)]-5-(1,1,1-trifluoromethyl)phenyl]methyl]benzamide

Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.33 mL, 2.0 mmol)is added to a stirred mixture of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg,1.0 mmol),3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine (220mg, 1.0 mmol) and triethylamine (560 μL, 4.0 mmol) in 5 mLN,N-dimethylformamide at 10° C. After stirring for 3 hours at 60° C.,the mixture is treated with saturated aqueous solution of sodiumhydrogen carbonate and extracted three times with ethyl acetate. Thecombined extracts are dried (MgSO₄), filtered and the solvent isevaporated off under reduced pressure to afford a crude product which isrecrystallised from ethylacetate to give the title compound as acrystalline solid, m.p. 253-258° C.

Example 693-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-N-[(4-methyl-1-piperazinyl)methyl]-benzamide

Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.50 mL, 3.0 mmol)is added to a stirred mixture of3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (438 mg, 1.5mmol), 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine (308 mg, 1.5 mmol)and triethylamine (840 μL, 3.0 mmol) in 10 mL N,N-dimethylformamide at10° C. After stirring for 12 hours at 60° C., the mixture is treatedwith an aqueous solution of sodium hydrogen carbonate and extractedthree times with ethyl acetate. The combined extracts are washed withwater, and the solvent is evaporated off under reduced pressure to givea residue. The residue is resuspended in water and filtered to affordthe crude product which is recrystallised from tetrahydrofuran-ethylacetate to giveN-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-N-[(4-methyl-1-piperazinyl)-methyl]benzamideas a crystalline solid, m.p. 220-224° C.

Example 69a 3-[(Aminoiminomethyl)amino]-4-methylbenzoic acid methylester mononitrate

Utilising the procedure described in Example 1a, but with 3-aminobenzoicacid methyl ester (Fluka, Buchs, Switzerland) in lieu of3-amino-4-methylbenzoic acid ethyl ester, afforded the title compound asa crystalline solid, m.p. 170-172° C.

Example 69b 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid methylester

Utilising the procedure described in Example 1b, but with theintermediate of Example 69a in lieu of4-methyl-3-[(aminoiminomethyl)amino]-4-methylbenzoic acid ethyl estermononitrate, afforded the title compound as a crystalline solid, m.p.195-200° C.

Example 69c 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid

Utilising the procedure described in Example 1c, but with theintermediate of Example 69b in lieu of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid ethylester, afforded the title compound as a crystalline solid, m.p. 285-293°C.

Example 703-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-N-[(3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but with3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)benzeneamine inlieu of 4-[(4-methyl-1-piperazinyl)methyl]benzene-amine, afforded3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)phenyl]benzamideas a crystalline solid, m.p. 213-215° C.

Example 714-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]-phenyl]benzamide

Utilising the procedure described in Example 3, but employing3-[3-(1H-imidazol-1-yl)propoxy]-benzenamine (Takao Nishi et al., JP10182459) in lieu of 1-(2-pyridyl)piperazine, afforded the titlecompound as a solid. ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.12-2.21 (m, 2H);2.33 (s, 3H); 3.87 (t, 2H); 4.13 (t, 2H); 6.66 (dd, 1H); 6.87 (s, 1H);7.15-7.26 (m, 2H); 7.32-7.42 (m, 2H); 7.44-7.52 (m, 3H); 7.61 (s, 1H);7.70 (d, 1H); 8.24 (s, 1H); 8.43 (d, 1H); 8.53 (d, 1H); 8.67 (d, 1H);9.13 (s, 1H); 9.26 (br. s, 1H); 10.13 (s, 1H).

Example 724-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide

Utilising the procedure described in Example 3, but employing3-[2-(1H-imidazol-1-yl)ethoxy]-benzenamine (Rolf Paul et al., Journal ofMedicinal Chemistry (1993), 36(19), 2716-25) in lieu of1-(2-pyridyl)piperazine, afforded the title compound as a crystallinesolid. ¹H-NMR (400 MHz, DMSO-d₆, δ): 2.34 (s, 3H); 4.22 (t, 2H); 4.37(t, 2H); 6.68 (dd, 1H); 6.90 (s, 1H); 7.21-7.27 (m, 2H); 7.36-7.43 (m,2H); 7.46-7.53 (m, 3H); 7.67-7.74 (m, 2H); 8.25 (br. s, 1H); 8.44 (dt,1H); 8.54 (d, 1H); 8.68 (dd, 1H); 9.15 (s, 1H); 9.27 (br. d, 1H); 10.15(s, 1H).

Example 734-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethylphenyl]benzamide

Utilising the procedure described in Example 69, but employingN-ethyl-2-(trifluoromethyl)-1,4-benzenediamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine,afforded the title compound as a crystalline solid, m.p. 178-180° C.

The aniline is prepared as follows:

Example 73a N-ethyl-2-(trifluoromethyl)-1,4-benzenediamine

A mixture of 2-bromo-5-nitrobenzotrifuoride (Lancaster Synthesis, GmbH;5.4 g, 20 mmol) and a solution of ethylamine in ethanol (50 mL of 2M,100 mmol) is heated at 80° C. for 18 hours in a steel pressure vessel.The mixture is then cooled and the solvent is evaopated off underreduced pressure to yield the crude product which is purified by columnchromatography (silica gel, eluent 20% ethyl acetate in hexane) toafford N-ethyl-4-nitro-6-(trifluoromethyl)-benzenamine as yellow oil.This product is dissolved in ethanol (180 mL) and hydrogenated atatmospheric pressure over Raney nickel (0.5 g) at 45° C. The calculatedamount of hydrogen is taken up in 50 hours. The mixture is then filteredand the solvent is evaporated off under reduced pressure to yield thecrude product which is purified by chromatography (silica gel; eluent50% ethyl acetate in hexane) and recrystallised from ether-hexane togive the title compound as a beige crystalline solid. ¹H-NMR (400 MHz,DMSO-d₆): 1.11 (t, 3H), 3.05 (m, 2H), 4.18 (br t, 1H), 4.66 (br.s, 2H),6.58-6.64 (m, 1H) and 6.68-6.75 (m, 2H).

Example 744-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-[4-diethylamino)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employingN,N-diethyl-2-(trifluoromethyl)-1,4-benzenediamine (Toshio Niwa, DE3524519) in lieu of 1-(2-pyridyl)piperazine, afforded the title compoundas a crystalline solid, m.p. 128-131° C.

Example 75(±)-4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[(2-hydroxy-propyl)amino]-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing(±)-1-[[4-amino-2-(trifluoromethyl)phenyl]amino]-2-propanol (TsutomuMano, EP 299497) in lieu of 1-(2-pyridyl)piperazine, afforded the titlecompound as a crystalline solid, m.p. 184-186° C.

Example 764-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxy-ethyl)amino]-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employingN,N-bis(2-methoxyethyl)-2-(trifluoromethyl)-1,4-benzenediamine (ToshioNiwa, DE 3524519) in lieu of 1-(2-pyridyl)piperazine, afforded the titlecompound as a crystalline solid, m.p. 156-157° C.

Example 774-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)-benzenamine (AnthonyDavid Baxter, WO 0119800) in lieu of 1-(2-pyridyl)piperazine, affordedthe title compound as a crystalline solid, m.p. 214-217° C.

Example 784-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing4-(1-piperidinyl)-3-(trifluoromethyl)-benzenamine (Leping Li, WO0151456) in lieu of 1-(2-pyridyl)piperazine, afforded the title compoundas a crystalline solid, m.p. 201-202° C.

Example 794-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing4-(1-pyrrolidinyl)-3-(trifluoromethyl)-benzenamine (Steven Lee Bender WO0153274) in lieu of 1-(2-pyridyl)piperazine afforded the title compoundas a crystalline solid, m.p. 129-130° C.

Example 804-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing4-(4-morpholinyl)-3-(trifluoromethyl)-benzenamine (Steven Lee Bender WO0153274) in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 216-218° C.

Example 814-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-phenyl-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing4-(phenyl)-3-(trifluoromethyl)-benzenamine in lieu of1-(2-pyridyl)piperazine afforded the title compound as a crystallinesolid, m.p. 172-174° C.

The aniline is prepared as follows:

Example 81a 4-(Phenyl)-3-(trifluoromethyl)benzenamine

Phenyl boronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol),Palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2mmol) and aqueous potassium carbonate solution (50 mL of 1 M) is addedto a stirred solution of 2-bromo-5-nitrobenzotrifuoride (LancasterSynthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 mL) andheated at 120° C. under an argon atmosphere for 1 h. The mixture is thenevaporated to dryness under reduced pressure and the residue is treatedwith water (100 mL) and extracted with ethyl acetate (3×80 mL). Thecombined extracts are washed (brine), dried (MgSO4), filltered and thesolvent is evorated off under reduced pressure to afford4′-nitro-2′-(trifluoromethyl)-[1,1′-Biphenyl]. The biphenyl is dissolvedin ethanol (200 mL) and hydrogenated at atmospheric pressure over Raneynickel (2 g) at 22° C. The calculated amount of hydrogen is taken up in11 hours. The mixture is then filtered and the solvent is evaporated offunder reduced pressure to yield the crude product which is purified bychromatograghy (silica gel; eluent ethyl acetate) to give the titlecompound as a brown oil. ¹H-NMR (400 MHz, DMSO-d₆): 5.62 (br.s, 2H),6.80 (dd, 1H), 6.96 (d, 1H), 6.99 (d, 1H), 7.19-7.23 (m, 2H), and7.29-7.39 (m, 3H).

Example 824-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide

Utilising the procedure described in Example 69, but employing4-(3-pyridinyl)-3-(trifluoromethyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 276-280° C.

The aniline is prepared as follows:

Example 82a 4-(3-Pyridinyl)-3-(trifluoromethyl)benzenamine

A stirred solution of 2-bromo-5-nitrobenzotrifuoride (LancasterSynthesis, GmbH; 3.37 g, 12.5 mmol) and 3-(tri-n-butylstannyl)pyridine(Maybridge Chemical Co. Ltd., England; 5.0 g, 13.6 mmol) in xylene (75mL) was purged with argon for 10 minutes at 20° C.Tetrakis(triphenylphosphine)palladium (0) (1.4 g, 1.25 mmol) is thenadded and the resulting mixture is heated at 130° C. for 24 hours underan argon atmosphere. The mixture is then cooled, treated with an aqueoussolution of sodium hydroxide (150 mL of 0.1 M) and purged with air for 2hours. The resulting mixture is then diluted with ethylacetate (200 mL)and filtered. The orgainic phase is then sequentially washed with water(2×80 mL) and saturated aqueous sodium chloride (1×80 mL), dried(MgSO₄), filtered and the solvent is evaporated off under reducedpressure to yield the crude product which is purified by columnchromatography (silica gel, eluent 50% ethyl acetate in hexane) toafford 3-[(4-nitro-3-(trifluoromethyl)phenyl]pyridine. This product isdissolved in ethanol (200 mL) and hydrogenated at atmospheric pressureover Raney nickel (0.23 g) at 22° C. The calculated amount of hydrogenis taken up in 24 hours. The mixture is then filtered and the solvent isevaporated off under reduced pressure to yield the crude product whichis purified by chromatography (silica gel; eluent 50% ethyl acetate inhexane) and recrystallised from ether-hexane to give the title compoundas a colourless crystalline solid, m.p. 92-93° C.

Example 834-Methyl-3-[[4(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing4-(1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine (Steven Lee BenderWO 0153274) in lieu of 1-(2-pyridyl)piperazine afforded the titlecompound as a crystalline solid, m.p. 226-229° C.

Example 844-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine inlieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine,afforded the title compound as an amorphous solid.

The aniline is prepared as follows:

Example 84a4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine

A mixture of 2-bromo-5-nitrobenzotrifuoride (Lancaster Synthesis, GmbH;6.0 g, 22 mmol) and 2,4-dimethylimidazole (10.6, 110 mmol) is heated at120° C. for 36 hours under an argon atmosphere. The mixture is thencooled and the residue is treated with water (150 mL) and extracted withethyl acetate (3×80 mL). The combined extracts are washed (brine), dried(MgSO₄), filtered and the solvent is evaporated off under reducedpressure to yield the crude product which is purified by columnchromatography (silica gel, eluent ethyl acetate) to afford1-[4-nitro-2-(trifluoromethyl)phenyl]-1H-imidazole as yellow crystallinesolid. This product is dissolved in ethanol (290 mL) and hydrogenated atatmospheric pressure over Raney nickel (1.15 g) at 25° C. The calculatedamount of hydrogen is taken up in 14 hours. The mixture is then filteredand the solvent is evaporated off under reduced pressure to yield thecrude product which is purified by recrystallisation from ether-hexaneto give the title compound as a crystalline solid, m.p. 163-164° C.

Example 854-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 154-163° C.

The aniline is prepared as follows:

Example 85a4-(4-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine

Utilising the procedure described in Example 84a, but employing4(5)-methyl-1H-imidazole in lieu of 2,4-dimethylimidazole, afforded thetitle compound as a beige crystalline solid, m.p. 141-143° C.

Example 864-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 154-163° C.

The aniline is prepared as follows:

Example 86a4-(2-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine

Utilising the procedure described in Example 84a, but employing2-methyl-1H-imidazole in lieu of 2,4-dimethylimidazole, afforded thetitle compound as a colourless crystalline solid, m.p. 117-119° C.

Example 874-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonyl]phenyl]benzamide

Utilising the procedure described in Example 69, but employing3-amino-5-(4-morpholinyl)-N-(methyl)-benzamide in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine,afforded the title compound as a crystalline solid, m.p. 153-156° C.

The aniline is prepared as follows:

Example 87a 3-Bromo-5-nitro-benzoic acid, 1,1-dimethylethyl ester

A solution of n-butyllithium in hexane (12.8 mL of 2.5 M, 32 mmol) isadded with stirring to t-butanol (46 mL) at 25° C. under an argonatmosphere. After 30 min the mixture is treated dropwise with a solutionof 3-bromo-5-nitro-benzoyl chloride (J. Mindl, Collect. Czech. Chem.Commun. (1973), 38, 3496-505; 32 mmol) in dry THF (40 mL) and stirredfor a further 17 h. The mixture is then treated with ether (250 mL) andwashed with brine. The ether solution was dried (MgSO₄) and the solventis evaporated off under reduced pressure to give the crude product whichis purified by column chromatography (silica gel, eluent 20% ethylacetate in hexane) and recrystallised from ether-hexane to afford thetitle compound as colourless crystalline solid, m.p. 77-78° C.

Example 87b 3-(4-Morpholinyl)-5-nitro-benzoic acid, 1,1-dimethylethylester

A stirred mixture of 3-bromo-5-nitro-benzoic acid, 1,1-dimethylethylester (example 86a; 3.02 g, 10 mmol) and morpholine (1.22 mL, 14 mmol)in toluene (50 mL) is treated with sodium t-butylate (1.34 g, 14 mmol),tri-t-butylphosphine (3 mL, 1.5 mmol) andtris-(dibenzylidene-acetone)dipalladium[0] (0.45 g, 0.5 mmol) under anargon atmosphere, and then heated at 60° C. for 18 h. The mixture isdiluted with ethyl acetate (150 mL), filtered, washed with brine (2×50mL), dried (MgSO₄) and the solvent is evaporated off under reducedpressure to give the crude product which is purified by columnchromatography (silica gel, eluent 15% ethyl acetate in hexane) andrecrystallised from ethyl acetate-hexane to afford the title compound ascolourless crystalline solid, m.p. 116-118° C.

Example 87c 3-(4-Morpholinyl)-5-nitro-benzoic acid, methyl ester

A mixture of 3-(4-morpholinyl)-5-nitro-benzoic acid, 1,1-dimethylethylester (Example 87b; 0.77 g, 2.5 mmol),1,8-diazabicyclo[5,4,0]undec-7-ene (0.56 mL, 3.75 mL), and potassiumbromide (1.09 g, 12.5 mmol) in methanol (25 mL) is stirred at 90° C. for250 min. The cooled mixture is then added to hydrochloric acid (50 mL of0.1 M) and extracted with ethyl acetate (3×100 mL). The combined extactsare washed with saturated aqueous sodium hydro-carbonate (2×25 mL),water (2×25 mL) and brine (2×50 mL), dried (MgSO₄) and the solvent isevaporated off under reduced pressure to give the crude product which ispurified by recrystallisation from ethyl acetate-hexane to afford thetitle compound as yellow crystalline solid.

Example 87d 3-(4-Morpholinyl)-5-nitro-N-(methyl)-benzamide

A stirred solution of 3-(4-morpholinyl)-5-nitro-benzoic acid, methylester (Example 86c; 0.53 g, 2 mmol) in toluene (5 mL) under an argonatmosphere, is treated with a mixture of methylamine hydrochloride (0.27g, 4 mmol), trimethylaluminium (2 mL of a 2 M solution in toluene, 4mmol) in toluene (5 mL) and heated at 60° C. for 18 h. The cooledmixture is then treated with hydrochloric acid (10 mL of 2 M), stirredfor 5 min and then treated with aqueous sodium hydroxide (5 mL of 4 M).The mixture is then treated with water (100 mL) and extracted with ethylacetate (3×100 mL). The combined extacts are washed with brine (2×50mL), dried (MgSO₄) and the solvent is evaporated off under reducedpressure to give the crude product which is purified byrecrystallisation from ethyl acetate to afford the title compound asyellow crystalline solid, m.p. 204-207° C.

Example 87e 3-Amino-5-(4-Morpholinyl)-N-(methyl)-benzamide

A solution of 3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide (Example86d; 300 mg, 1.12 mmol) in ethanol (20 mL) is hydrogenated atatmospheric pressure over Raney nickel (0.2 g) at 25° C. The calculatedamount of hydrogen is taken up in 19 hours. The mixture is then filteredand the solvent is evaporated off under reduced pressure to yield thecrude product which is purified by recrystallisation from ethyl acetateto give the title compound as a beige crystalline solid, m.p. 201-204°C.

Example 884-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing3-amino-5-(trifluoromethyl)-N-(methyl)-benzamide in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine,afforded the title compound as a crystalline solid, m.p. 245-249° C.

Example 88a 3-Amino-5-(trifluoromethyl)-N-(methyl)-benzamide

Utilising the procedure described in Example 86e, but employingα,α,α-trifluoro-N-methyl-5-nitro-m-toluamide (Dean E. Welch, J. Med.Chem. (1969),12, 299-303) in lieu of3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide, afforded the titlecompound as a beige crystalline solid, m.p. 113-115° C.

Example 894-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N[5-(3-pyridinyl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing5-(3-pyridinyl)-3-(trifluoro-methyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine,afforded the title compound as a crystalline solid, m.p. 275-279° C.

The aniline is prepared as follows:

Example 89a 5-(3-Pyridinyl)-3-(trifluoromethyl)benzenamine

A stirred solution of 3-amino-5-bromo-benzotrifuoride (Apollo, England;1.12 g, 5 mmol) and 3-(tri-n-butylstannyl)pyridine (Maybridge ChemicalCo. Ltd., England; 2.0 g, 5.4 mmol) in xylene (30 mL) was purged withargon for 10 minutes at 20° C. Tetrakis(triphenylphosphine)-palladium(0) (1.16 g, 1.0 mmol) is then added and the resulting mixture is heatedat 140° C. for 36 hours under an argon atmosphere. The mixture is thencooled, treated with an aqueous solution of sodium hydroxide (100 mL of0.1 M) and purged with air for 2 hours. The resulting mixture is thendiluted with ethylacetate (200 mL) and filtered. The orgainic phase isthen sequentially washed with water (2×80 mL) and saturated aqueoussodium chloride (1×80 mL), dried (MgSO₄), filtered and the solvent isevaporated off under reduced pressure to yield the crude product whichis purified by column chromatography (silica gel, eluent ethyl acetate)to afford the title compound as a brown oil. ¹H-NMR (400 MHz, DMSO-d₈,δ): 5.73 (br s, 2H), 6.83 (dd, 1H), 6.99 (d, 1H), 7.04 (d, 1H), 7.39(dd, 1H), 7.64 (d, 1H), 8.42 (m, 1H) and 8.53 (dd, 1H).

Example 904-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing5-(4-morpholinyl)-3-(trifluoromethyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 208-211° C.

The aniline is prepared as follows:

Example 90a [3-Bromo-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester

A mixture of 3-amino-5-bromo-benzotrifuoride (Apollo, England; 12 g, 50mmol), di-t-butyl-dicarbonate (12 g, 55 mmol) and4-dimethylaminopyridine (0.61 g, 5 mmol) in acetonitrile (100 mL) isstirred at 60° C. for 8 h. The solvent is then evaporated off underreduced pressure to yield the crude product which is purified by columnchromatography (silica gel, eluent 10% ethyl acetate in hexane) andrecrystallised from hexane to afford the title compound as a colourlesscrystalline solid, m.p. 113-115° C.

Example 90b [3-(4-Morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester

Utilising the procedure described in Example 86b but employing[3-bromo-5-(trifluoromethyl)-phenyl]-carbamic acid, 1,1-dimethylethylester (Example 90a) in lieu of 3-bromo-5-nitro-benzoic acid,1,1-dimethylethyl ester, afforded the title compound as a crystallinesolid, m.p. 146-148° C.

Example 90c 5-(4-Morpholinyl)-3-(trifluoromethyl)-benzenamine

[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester (Example 90b; 1.7 g, 5 mmol) is treated with asolution of hydrogen chloride in isopropanol (30 mL of 4 M) and heatedat 60° C. for 5 h. The solvent is evaporated off under reduced pressureand the residue is treated with aqueous sodium hydrogen carbonatesolution (80 mL) and extracted with ethyl acetate (3×80 mL). Thecombined extacts are washed with brine (2×50 mL), dried (MgSO₄) and thesolvent is evaporated off under reduced pressure to give the crudeproduct which is purified by recrystallisation from ether-hexane toafford the title compound as yellow crystalline solid, m.p. 96-97° C.

Example 914-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 242-247° C.

The was aniline is prepared as follows:

Example 91a3-(2-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile

A mixture of 3-fluoro-5-(trifluoromethyl)-benzonitrile (LancasterSynthesis GmbH; 17 g, 89 mmol) and 2-methylimidazole (Fluka, Buchs,Switzerland; 22.2 g, 270 mmol) in N,N-dimethylacetamide (80 mL) isstirred at 145° C. for 19 h. The solvent is evaporated off under reducedpressure and the residue is dissolved in ethyl acetate (200 mL). Thesolution is washed with brine (200 mL), dried (Na₂SO₄) and the solventis evaporated off under reduced pressure to give the crude product whichis purified by recrystallisation from ether-hexane to afford the titlecompound as yellow crystalline solid, m.p. 132-134° C.

Example 91b 3-(2-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoicacid

A solution of3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example91a; 16.7 g, 66 mmol) in dioxane (300 mL) is added to an aqueoussolution of sodium hydroxide (275 mL of 1 M) and the mixture is heatedat 95° C. for 18 h. The solvent is evaporated off under reduced pressureand the residue is neutralised with hydrochloric acid (1 M) andextracted with butanol (2×250 mL). The solvent is evaporated of underreduced pressure to give the title compound. ¹H-NMR (400 MHz, DMSO-d₆,δ): 7.17 (s, 1H); 8.03 (s, 1H); 8.12 (s, 1H); 8.35 (s, 1H); 8.41 (s,1H); 8.53 (s, 1H); 13.90 (br., 1H).

Example 91c[3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester

Triethylamine (5.23 mL, 37.5 mmol) is added to a stirred suspension of3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example91 b; 6.8 g, 25 mmol) in t-butanol (200 mL). Diphenylphosphorylazide(7.6 g, 27.5 mmol) is added to the resulting solution and the mixture isheated 80° C. for 16 h. The solvent is evaporated off under reducedpressure and the residue is treated with water (100 mL) and extractedwith ethyl acetate (2×100 mL). The combined extracts are washed withbrine (100 mL), dried (Na₂SO₄) and the solvent is evaporated off underreduced pressure to give the crude product which is purified by columnchromatography (silica gel, eluent 2% ethanol in ethyl acetate) andrecrystallised from ether-hexane to afford the title compound as acolourless crystalline solid, m.p. 203-208° C.

Example 91d5-(2-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine

Utilising the procedure described in Example 90c but employing[3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester (Example 91c) in lieu of[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester, afforded the title compound as a yellowcrystalline solid, m.p. 130-133° C.

Example 924-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 235-236° C.

The was aniline is prepared as follows:

Example 92a3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile

Utilising the procedure described in Example 91a, but employing4-methyl-1H-imidazole in lieu of 2-methylimidazole, afforded the titlecompound as a crystalline solid, m.p. 127-128° C.

Example 92b 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoicacid

Utilising the procedure described in Example 91b, but employing3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example92a) in lieu of3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile, affordedthe title compound as a crystalline solid, m.p. >300° C.

Example 92c[3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester

Utilising the procedure described in Example 91c, but employing3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example92b) in lieu of3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid, affordedthe title compound as a crystalline solid, m.p. 186-188° C.

Example 92d5-(2-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine

Utilising the procedure described in Example 91d, but employing[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester (Example 92c) in lieu of[3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester, afforded the title compound as a colourlesscrystalline solid, m.p. 127-131° C.

Example 934-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of1-(2-pyridyl)piperazine, afforded the title compound as a crystallinesolid, m.p. 231-233° C.

The aniline is prepared as follows:

Example 93a3-(5-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile

Utilising the procedure described in Example 91a, but employing4-methyl-1H-imidazole in lieu of 2-methylimidazole, afforded the titlecompound as a crystalline solid, m.p. 99-101° C.

Example 93b 3-(5-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoicacid

Utilising the procedure described in Example 91b, but employing3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example93a) in lieu of3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile, affordedthe title compound as a colourless crystalline solid, m.p. 243-245° C.

Example 93c[3-(5-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester

Utilising the procedure described in Example 91c, but employing3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example93b) in lieu of3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid, affordedthe title compound as a crystalline solid, m.p. 169-171° C.

Example 93d5-(5-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine

Utilising the procedure described in Example 91d, but employing[3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester (Example 93c) in lieu of[3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester, afforded the title compound as a colourlesscrystalline solid, m.p. 131-133° C.

Example 944-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 69, but employing3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)-benzenamine in lieu of3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine,afforded the title compound as a crystalline solid, m.p. 192-194° C.

The aniline is prepared as follows:

Example 94a[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester

Utilising the procedure described in Example 87b, but employing1-methyl-1-piperazine in lieu of morpholine, afforded the title compoundas a crystalline solid, m.p. 225° C.

Example 94b 3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)-benzenamine

Utilising the procedure described in Example 90c, but employing[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester (Example 94a) in lieu of[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid,1,1-dimethylethyl ester, afforded the title compound as oil. ¹H-NMR (400MHz, DMSO-d₆): 2.20 (s, 3H), 2.42 (m, 4H), 3.07 (m, 4H), 3.32 (br s,2H), 5.34 (s, 1H) and 6.31 (s, 2H).

Example 954-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in Example 3, but employing2-(1-pyrrolidinyl)-5-(trifluoromethyl)-benzenamine (Lancaster SynthesisLtd.; Yasuhiro Ohtake et al., WO 9965874) in lieu of1-(2-pyridyl)piperazine, afforded the title compound as a crystallinesolid. ¹H-NMR (400 MHz, DMSO-d₆): 1.77-1.82 (m, 4H); 2.34 (s, 3H);3.31-3.37 (m, 4H); 6.86 (d, 1H); 7.34-7.44 (m, 2H); 7.47 (d, 1H);7.49-7.53 (m, 1H); 7.73 (dd, 1H); 8.27 (d, 1H); 8.43 (dt, 1H); 8.53 (d,1H); 8.69 (dd, 1H); 9.13 (s, 1H); 9.27 (d, 1H); 9.96 (s, 1H).

Example 963-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide

Utilising the procedure described in example 1, but employing3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid in lieu of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid and5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu offurfurylamine, afforded the title compound as as pale-yellow crystallinesolid, m.p. 264-266° C.

Example 96a 3-[(Aminoiminomethyl)amino]-benzoic acid ethyl estermononitrate

Utilising the procedure described in example 1a but employing3-amino-benzoic acid ethyl ester (Fluka, Buchs, Switzerland) in lieu of3-amino-4-methylbenzoic acid ethyl ester, afforded the title compound asa crystalline solid, m.p. 170-172° C.

Example 96b 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid ethylester

Utilising the procedure described in example 1b but employing3-[(aminoiminomethyl)amino]-benzoic acid ethyl ester mononitrate in lieuof 3-[(aminoiminomethyl)amino]-4-methyl-benzoic acid ethyl estermononitrate, afforded the title compound as a crystalline solid, m.p.197-199° C.

Example 96c 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid

Utilising the procedure described in example 1c but employing3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid ethyl ester inlieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acidethyl ester, afforded the title compound as a crystalline solid, m.p.291-295° C.

Example 97 Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula I mentioned in the precedingExamples, are prepared as follows: 250 g pulverized active ingredient issuspended in 2L Lauroglykol® (propylene glycol laurate, Gattefossé S.A., Saint Priest, France) and ground in a wet pulverizer to produce aparticle size of about 1 to 3 μm. 0.419 g portions of the mixture arethen introduced into soft gelatin capsules using a capsule-fillingmachine.

Example 98 Pharmacokinetic Data

The compound of formula I to be tested is formulated for administrationto female OF1 mice from IFACREDO, France, by first dissolving in NMP,and then by diluting with PEG300 to a final concentration of 10% v/vNMP: 90% v/v PEG300, producing a clear solution of the compound. Theconcentrations were adjusted to deliver a constant volume of 10 mL/kgbody weight. The compound is prepared immediately before use. Theformulated compound is administered perorally by gavage to providedosages of 50 mg/kg. At the allotted time points mice (4 at each time)are anesthetized with 3% isoflurane in medical oxygen and blood samplesare obtained by heart puncture into heparinized tubes (ca. 30 IU/mL).The animals are subsequently killed without recovering from theanesthetic. Plasma is prepared from the blood by centrifugation (10,000g, 5 min) and either analyzed immediately or stored frozen at −70° C.

The plasma samples (10-250 μL) are e.g. spiked with 5 μL of internalstandard, mixed with 200 μL 0.1 M NaOH and 500 μL chloroform in a 1.5 mLEppendorf tube and shaken vigorously for 10 minutes on an Eppendorfmixer. Thereafter, the mixture is centrifuged (3 min at 10'000×g), theorganic phase transferred to a second Eppendorf tube and evaporated todryness in a vacuum centrifuge (Speedvac 5301). The dry residue e.g. isdissolved in 250 μL of 10% v/v Acetonitrile in water containing 0.1%formic acid. The subsequent analysis is carried out e.g. by HPLC/MS-MSusing an Agilent 1100 Series (Agilent, Palo Alto, Calif., USA) HPLCsystem with vacuum degasser, binary pump, and thermostated columncompartment combined with a cooled autosampler system (HTS PAL, CTCAnalytics, Zwingen, Switzerland). The sample (5-15 μL) is injected e.g.onto an Ultra Phenyl column (particle size 3 μm, 50×1 mm; Restek,Bellefonte, USA) with a guard column (4×2 mm) of the same material(Phenomenex, Torrance, USA). After equilibration e.g. with water and alatency period of 1 min the sample is eluted e.g. by a linear gradientof 0-100% acetonitrile in water containing 0.2% v/v formic acid over aperiod of 11 min at a flow rate of 60 μL/min. The column is prepared forthe next sample e.g. by re-equilibrating for 3 min with 100% water tothe starting conditions. The separation is performed e.g. at a columntemperature of 40° C. The column effluent is introduced e.g. directlyinto the ion source of a triple stage quadropole mass spectrometer(Quattro Ultima™, Micromass, Manchester, UK) controlled by Masslynx™ 3.5software (Micromass, Manchester, UK) using as ionization techniqueelectrospray ionization positive mode (ESI+). The compound is detectedby MS/MS following fragmentation of the parent ions. The limit ofquantitation is determined at e.g. 0.002 nmol/L. A calibration curve isconstructed with known amounts of compound including a fixed amount ofinternal standard in plasma which is processed as described above. Theconcentration of unknown samples is calculated from a plot of the peakarea ratio of the selected daughter ion of the analyte to the product ofits internal standard (ordinate) against the nominal concentration(abscissa). Regression analysis is performed using Quanlynx™, Masslynx™software 3.5 (Micromass, Manchester, UK).

Example 99 In vitro Inhibition Data

Enzymatic (c-Abl, KDR, Flt3) in vitro inhibition data are presented as %inhibition at 10 μM. The measurements are made as described above in thegeneral description. Example Abl % @ 10 μM KDR % @ 10 μM Flt3% @ 10 μM 1 51 57  2 97 73  3 66 71  4 77 46  5 71 60  6 51 56  7 72 45  8 70 81 9 44 39 10 57 48 11 53 41 12 22 33 13 78 48 14 49 54 15 60 23 16 42 1017 54 62 18 56 62 19 41 33 20 56 22 21 30 93 22 59  7 23 90 67 24 80 7025 44 73 26 55 56 27 54 51 28 73 61 29 78 30 57 37 31 68 83 32 90 37 3397 51 34 73 89 35 27 47 36 57 77 37 28 82 38 74 91 39 64 74 40 65 78

1. A compound of formula

wherein R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, or phenyl-lower alkyl; R₂ represents hydrogen, lower alkyl,optionally substituted by one or more identical or different radicalsR₃, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono-or bicyclic heteroaryl group comprising zero, one, two or three ringnitrogen atoms and zero or one oxygen atom and zero or one sulfur atom,which groups in each case are unsubstituted or mono- or polysubstituted;and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an arylgroup, or a mono- or bicyclic heteroaryl group comprising zero, one, twoor three ring nitrogen atoms and zero or one oxygen atom and zero or onesulfur atom, which groups in each case are unsubstituted or mono- orpolysubstituted; or wherein R₁ and R₂ together represent alkylene withfour, five or six carbon atoms optionally mono- or disubstituted bylower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy,amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl orpyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylenewith one oxygen and three or four carbon atoms; or azaalkylene with onenitrogen and three or four carbon atoms wherein nitrogen isunsubstituted or substituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl,N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, loweralkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl,pyrimidinyl, or pyrazinyl; R₄ represents hydrogen, lower alkyl, orhalogen; and a N-oxide or a pharmaceutically acceptable salt of such acompound.
 2. compound of formula I according to claim 1 wherein R₁represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, or phenyl-lower alkyl; R₂ represents hydrogen, lower alkyl,optionally substituted by one or two identical or different radicals R₃,cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- orbicyclic heteroaryl group comprising one, two or three nitrogen atoms orone sulfur atom, which aryl and heteroaryl groups in each case areunsubstituted or mono- or polysubstituted; and R₃ represents hydroxy,lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono-or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino,cycloalkyl, heterocyclyl, an aryl group, furanoyl, thienoyl, or a mono-or bicyclic heteroaryl group comprising one, two or three ring nitrogenatoms, zero or one ring oxygen atom and zero or one ring sulphur atom,which aryl and heteroaryl groups in each case are unsubstituted or mono-or polysubstituted; or wherein R₁ and R₂ together represent alkylenewith four or five carbon atoms, optionally mono- or disubstituted bylower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy,amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl;benzalkylene with four or five carbon atoms in the alkylene group;oxaalkylene with one oxygen and three or four carbon atoms, orazaalkylene with one nitrogen and three or four carbon atoms whereinnitrogen is unsubstituted or substituted by lower alkyl, phenyl-loweralkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl,carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-loweralkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl,pyridinyl, pyrimidinyl, or pyrazinyl; R₄ represents hydrogen, loweralkyl, or halogen; and a N-oxide or a pharmaceutically acceptable saltof such a compound.
 3. A compound of formula I according to claim 1wherein R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl; R₂ representshydrogen, lower alkyl, optionally substituted by one or two identical ordifferent radicals R₃, cyclopentyl, benzcyclopentyl, cylcohexyl,pyrrolidinyl, oxazolinyl, piperidinyl, N-substituted piperidinyl,morpholinyl, azepinyl, oxo-azepinyl, oxazepinyl, phenyl, naphthalinyl,tetrahydronaphthalinyl or a mono- or bicyclic heteroaryl groupcomprising one or two nitrogen atoms, which phenyl, naphthalinyl andheteroaryl groups in each case are unsubstituted or mono- orpolysubstituted, thienyl, or lower alkoxycarbonyl-lower alkylthienyl;and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, lower alkylamino, di-lower alkylamino, phenylamino, N-loweralkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino,morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl,furyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- orbicyclic heteroaryl group comprising one or two nitrogen atoms, whichphenyl, naphthalinyl and heteroaryl group are unsubstituted or mono- orpolysubstituted; or wherein R₁ and R₂ together represent alkylene withfour or five carbon atoms, optionally mono- or disubstituted by loweralkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino,mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl;benzalkylene, with four or five carbon atoms in the alkylene group;oxaalkylene with one oxygen and four carbon atoms; or azaalkylene withone nitrogen and four carbon atoms wherein nitrogen is unsubstituted orsubstituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl,N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, loweralkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, orpyrazinyl; R₄ represents hydrogen, lower alkyl, or halogen; and aN-oxide or a pharmaceutically acceptable salt of such a compound.
 4. Acompound of formula I according to claim 1 wherein R₁ representshydrogen, lower alkyl, lower alkoxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, or phenyl-lower alkyl; R₂ representshydrogen; lower alkyl, optionally substituted by one radical R₃, by twophenyl groups, by two lower alkoycarbonyl groups, by phenyl and loweralkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl;cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; oxazolinyl;piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl;N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxo-azepinyl;oxazepinyl; phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- orbicyclic heteroaryl group comprising one or two nitrogen atoms, whichphenyl, naphthalinyl and heteroaryl groups in each case areunsubstituted or substituted by one or two substituents selected fromthe group consisting of lower alkyl, trifluoro-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, loweralkylamino-lower alkyl, di-lower alkylamino-lower alkyl,N-cyclohexyl-N-lower alkylamino-lower alkyl, loweralkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-loweralkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy,trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy,benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- ordisubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, 1H-imidazolyl, mono- or di-loweralkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-loweralkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl,phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio,phenylthio, phenyl, pyridyl, halogenyl, or benzoyl; thienyl; or loweralkoxycarbonyl-lower alkylthienyl; and R₃ represents hydroxy, loweralkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, carbamoylmono-or disubstituted by lower alkyl, phenyl or lower alkylene, amino,lower alkylamino, di-lower alkylamino, phenylamino, N-loweralkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino,morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl,furyl; phenyl, naphthalinyl, tetrahydronaphthalinyl, or a-mono- orbicyclic heteroaryl group comprising one or two nitrogen atoms, whichphenyl, naphthalinyl and heteroaryl group is unsubstituted orsubstituted by one or two substituents selected from the groupconsisting of lower alkyl, trifluoro-lower alkyl, loweralkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-loweralkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl,carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- ordisubstituted by lower alkyl, by hydroxy-lower alkyl or byloweralkoxy-lower alkyl, pyrrolidino, piperidino, morpholino,piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino,phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl,lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl,phenylsulfinyl, lower alkylthio, phenylthio, halogenyl, or benzoyl; orwherein R₁ and R₂ together represent alkylene with four or five carbonatoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl,phenyl, hydroxy, lower alkoxy, amino, benzoylamino, piperidino, pyridyl,pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms inthe alkylene group; oxaalkylene with one oxygen and four carbon atoms;or azaalkylene with one nitrogen and four carbon atoms wherein nitrogenis unsubstituted or substituted by lower alkyl, phenyl-lower alkyl,lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-loweralkyl, carbamoyl-lower alkyl N-mono- or N,N-disubstituted by loweralkyl, phenyl, lower alkylene or oxa-lower alkylene, cycloalkyl, loweralkoxycarbonyl, phenyl, methoxyphenyl, trifluoromethylphenyl,trifluoromethoxyphenyl, pyridinyl, pyrimidinyl, or pyrazinyl; R₄represents hydrogen or lower alkyl; and a N-oxide or a pharmaceuticallyacceptable salt of such a compound.
 5. A compound of formula I accordingto claim 1 wherein R₁ represents hydrogen, lower alkyl, loweralkoxy-lower alkyl, or benzyl; R₂ represents lower alkyl, optionallysubstituted by one radical R₃, by two phenyl groups, by two loweralkoycarbonyl groups, by phenyl and lower alkoxycarbonyl, or byhydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl;cylcohexyl; pyrrolidinyl; piperidinyl; N-lower alkylpiperidinyl;N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl;oxoazepinyl; phenyl; naphthalinyl; tetrahydronaphthalinyl; pyridyl;lower alkyl-pyridyl; quinolinyl; thienyl; loweralkoxycarbonylmethylthienyl; or phenyl substituted by one or twosubstituents selected from the group consisting of lower alkyl,trifluoro-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, loweralkylamino-lower alkyl, di-lower alkylamino-lower alkyl,N-cyclohexyl-N-lower alkylamino-lower alkyl, loweralkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-loweralkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy,trifluoro-lower alkoxy, 1-H-imidazolyl-lower alkoxy, lower alkanoyloxy,benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, loweralkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- ordisubstituted by lower alkyl, by hydroxy-lower alkyl or byloweralkoxy-lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl,pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino,morpholino, sulfamoyl, lower alkylsulfonyl, phenyl, pyridyl, halogenyl,or benzoyl; and R₃ represents hydroxy, lower alkoxy, lower alkanoyloxy,benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, loweralkylamino, di-lower alkylamino, phenylamino, N-loweralkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino,morpholino, imidazolino, oxoimidazolino, cyclopropyl, cyclopentyl,cyclohexyl, tetrahydrofuranyl, phenyl, naphthalinyl,tetrahydronaphthalinyl, furyl, a mono- or bicyclic heteroaryl groupcomprising one or two nitrogen atoms, which heteroaryl group isunsubstituted or mono- or disubstituted by lower alkyl, hydroxy andlower alkoxy, or phenyl substituted by one or two substituents selectedfrom the group consisting of lower alkyl, trifluoro-lower alkyl, loweralkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-loweralkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl,carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- ordisubstituted by lower alkyl, by hydroxy-lower alkyl or byloweralkoxy-lower alkyl, pyrrolidino, piperidino, morpholino,piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino,phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl,lower alkylsulfonyl, halogenyl, or benzoyl; or wherein R₁ and R₂together represent alkylene with four or five carbon atoms, optionallymono- or disubstituted by phenyl, hydroxy, amino, benzoylamino, orpiperidino; benzalkylene with four or five carbon atoms in the alkylenegroup; oxaalkylene with one oxygen and four carbon atoms; or azaalkylenewith one nitrogen and four carbon atoms wherein nitrogen isunsubstituted or substituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carbamoyl-lower alkylpyrrolidinocarbonyl-lower alkyl, morpholinocarbonyl-lower alkyl,cyclopentyl, lower alkoxycarbonyl, phenyl, methoxyphenyl,trifluoromethylphenyl, pyridinyl; pyrimidinyl, or pyrazinyl; R₄represents hydrogen or methyl; and a N-oxide or a pharmaceuticallyacceptable salt of such a compound.
 6. A compound of formula I accordingto claim 1 wherein R₁ represents hydrogen; R₂ represents phenylsubstituted by trifluoromethyl and optionally a further substituentselected from the group consisting of hydroxy-lower alkyl, loweralkylamino, hydroxy-lower alkylamino, di-lower alkylamino,1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, loweralkylcarbamoyl, pyrrolidino, piperidino, piperazino, loweralkylpiperazino, morpholino, lower alkoxy, trifluoro-lower alkoxy,phenyl, pyridyl, and halogenyl; R₄ represents methyl; and a N-oxide or apharmaceutically acceptable salt of such a compound.
 7. A compound offormula I according to claim 1 wherein R₁ represents hydrogen; R₂represents phenyl substituted by 3-trifluoromethyl and optionally afurther substituent selected from the group consisting of1-hydroxy-1-methylethyl, methylamino, ethylamino,2-hydroxy-1-propylamino, 2-hydroxy-2-propylamino, diethylamino,1H-imidazolyl, 2- and 4-methyl-1H-imidazolyl, carbamoyl,methylcarbamoyl, pyrrolidino, piperidino, piperazino,4-methylpiperazino, morpholino, methoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, phenyl, 2-, 3- and 4-pyridyl, chloro, and fluoro;R₄ represents methyl; and a N-oxide or a pharmaceutically acceptablesalt of such a compound.
 8. The compound of formula I according to claim1 wherein R₁ represents hydrogen; R₂ represents3-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)phenyl; R₄ representsmethyl; and a N-oxide or a pharmaceutically acceptable salt of such acompound.
 9. A compound according to any one of claim 1 wherein R₁ ishydrogen; R₂ represents phenyl which is mono- or disubstituted byimidazol-lower alkoxy, lower alkyl amino, trifluoromethyl, hydroxy loweralkyl amino, bis-(lower alkoxy lower alkyl) amino, lower alkylpiperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridyl,imidazolyl which is unsubstituted or mono- or disubstituted by loweralkyl or N-lower alkyl carbamoyl; R₄ is lower alkyl; and a N-oxide or apharmaceutically acceptable salt of such a compound.
 10. A compound offormula

wherein R₄ is methyl.
 11. A process for the synthesis of a compound ofthe formula

or an N-oxide or a salt thereof, wherein the symbols R₁, R₂ and R₄ areas defined in claim 1, characterized in that a compound of formula II

wherein R4 is as defined for a compound of formula I, or a derivativethereof wherein the carboxy group —COOH is in activated form, is reactedwith an amine of the formula IIIR₁—NH—R₂  (III) wherein R₁ and R₂ are as defined for a compound of theformula I, optionally in the presence of a dehydrating agent and aninert base and/or a suitable catalyst, and optionally in the presence ofan inert solvent; where the above starting compounds II and III may alsobe present with functional groups in protected form if necessary and/orin the form of salts, provided a salt-forming group is present and thereaction in salt form is possible; any protecting groups in a protectedderivative of a compound of the formula I are removed; and, if sodesired, an obtainable compound of formula I is converted into anothercompound of formula I or a N-oxide thereof, a free compound of formula Iis converted into a salt, an obtainable salt of a compound of formula Iis converted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula I is separated into the individualisomers.
 12. A pharmaceutical composition comprising as an activeingredient a compound of formula I according to claim 1 or a N-oxide ora pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier.
 13. A method for the treatment of adisease which responds to an inhibition of protein kinase activity,which comprises administering a compound of formula I according to claim1 or a N-oxide or a pharmaceutically acceptable salt thereof.
 14. Theuse of a compound of formula I according to claim 1 or a N-oxide or apossible tautomer thereof or of a pharmaceutically acceptable saltthereof for the preparation of a pharmaceutical composition for thetreatment of a disease which responds to an inhibition of protein kinaseactivity.